Search

Abstract 131: Cognitive Impairment Predicts Mortality in Patients with Heart Failure
- Howard Lan,
- Lee Ann Hawkins and
- Helme Silvet
Circulation: Cardiovascular Quality and Outcomes Volume 9, Issue suppl_21 March 2016

Abstract Export Citations

Abstract
Introduction: In our previously published study, we evaluated a Veteran cohort of 250 outpatients with heart failure (HF) and found 58% (144 of 250) incidence of previously undiagnosed cognitive impairment (CI). Previous studies have suggested that HF patients with CI have worse clinical outcomes including higher mortality but this has not been studied in the Veteran population.Methods: Current study was designed to prospectively follow this cohort of 250 patients. Cognitive function was previously evaluated in all patients at baseline using the St. Luis University Mental Status (SLUMS) exam. The primary outcome for this follow-up study was all-cause mortality. Data analysis including Cox regression analysis and Kaplan-Meier curves were generated using SPSS.Results: The study population was predominantly Caucasian (72%, 179 of 250) and male (99%, 247 of 250) with mean age of 69 ± 10 years. Mean follow up was 31 ± 11 months. During follow up, 26% (64 of 250) of patients died. Univariate and multivariate Cox proportional hazards regression analyses were performed and shown in Table 1. Using the SLUMS score, subjects were stratified into three groups: no CI (42%, 106 of 250), mild CI (42%, 104 of 250), and severe CI (16%, 40 of 250). Kaplan-Meier survival curves were generated to compare the three CI groups in Figure 1.Conclusion: Current study demonstrates that CI is an independent risk factor for mortality in outpatient HF patients. This is an important finding because CI is commonly unrecognized in this vulnerable population. Routine CI screening could help to identify those who are at greater risk for worse outcomes. Future studies are needed to derive possible interventions to improve outcomes in these patients.
Response to C-Reactive Protein and Cardiovascular Disease: Differences Between Humans and Mice
- Hui Y. Lan
- Alexander J. Szalai
Hypertension Volume 56, Issue 11 July 2010

Export Citations PDF/EPUB

Abstract
Abstract WMP22: High Baseline Blood Pressure is Associated With Better Collaterals but Not Better Clinical Outcome in Acute Ischemic Stroke
- Lan Hong,
- Xin Cheng,
- Longting Lin,
- Andrew Bivard,
- Qiang Dong and
- Mark Parsons
Stroke Volume 50, Issue Suppl_1

Abstract Export Citations

Abstract
Background and Purposes: The relationship between post-stroke blood pressure (BP), collaterals and functional outcome in acute ischemic stroke patients is still controversial. The purpose of this study is to explore the influence of post-stroke baseline BP on collateral flow and functional outcome in acute ischemic patients with large vessel occlusion/stenosis.Methods: Patients identified with large vessel occlusion/stenosis with baseline multimodal computed tomography, clinical data, follow-up imaging, and clinical outcomes recruited from 2011 to 2017 in the International Stroke Perfusion Imaging Registry (INSPIRE) were included in this study. A modified Rankin Score of 0-1 at 90 days after stroke was defined as an excellent functional outcome. Collateral flow was quantified by the volume of tissue with severely delayed contrast transit (delay time>6 seconds) within the delay time>3 seconds perfusion lesion. The association between baseline BP, collateral flow and 3-month outcome were retrospectively investigated using multivariate models.Results: There were 306 patients included in this study. With every increase of 10mmHg in baseline systolic BP, the odds of achieving an excellent functional outcome decreased by 12% in multivariate analysis (OR 0.88, 95% CI 0.76-0.995, P=0.048). Conversely, every increment of 10mmHg in baseline BP (regardless of systolic, diastolic and mean BP) was associated with better collateral flow, and was also associated with reduced final infarct volumes (FIV). In subgroup analysis of patients with major reperfusion, higher BP was associated with decreased FIV. For patients without reperfusion, higher BP was associated with increased FIV and decreased odds of a favorable clinical outcome.Conclusions: Higher baseline BP in acute ischemic stroke patients with large vessel occlusion/stenosis was associated with better collateral flow. However, for patients without reperfusion, higher baseline BP was associated with increased infarct growth, and led to an unfavorable clinical outcome. To our knowledge, this is the first time that the association between BP and collaterals has been quantified by perfusion imaging, and this is also the first study to demonstrate that higher BP is correlated with infarct growth.
Abstract TP261: Red Blood Cell Distribution Width is Associated With Collateral Flow and Infarct Volume Growth in Acute Stroke With Large Artery Atherosclerosis
- Lan Hong,
- Kun Fang,
- Yifeng Ling,
- Lumeng Yang,
- Wenjie Cao,
- Mark Parsons,
- Xin Cheng and
- Qiang Dong
Stroke Volume 50, Issue Suppl_1

Abstract Export Citations

Abstract
Background and Purpose: Red cell distribution width (RDW) has been recognized as a prognostic marker in cardiovascular diseases and stroke. Increased RDW is predictive of poor outcome and mortality in acute ischemic stroke patients. However, the underlying mechanisms are not fully understood. We aimed to explore the association between RDW, collateral flow, infarct volume growth, final infarct volume (FIV), and clinical outcomes in acute stroke patients with large artery atherosclerosis.Methods: This is a single-center retrospective cohort study based on a prospective registry of consecutive acute ischemic stroke patients within 6 hours of onset. Acute ischemic stroke identified with anterior circulation large artery atherosclerosis (LAA) with complete baseline and follow-up imaging (Non-contrast CT, CT Angiography, Perfusion CT) as well as clinical profiles were enrolled. Collaterals was assessed using the volume ratio between delay time (DT) >3s and DT>6s lesions. Baseline infarct core volume was defined by relative cerebral blood flow<30%. FIV was calculated by manually drawing regions of interest on the follow-up images. Infarct volume growth was determined from FIV minus baseline infarct core volume. A good functional outcome was defined as a 3-month modified Rankin Score of 0-2. The relationship between RDW, collaterals, infarct volume growth, FIV and clinical outcomes were evaluated using multivariate models.Results: A total number of 100 patients were included in this study. Multivariate adjusted general linear models revealed that increased RDW was associated with poorer collaterals (multivariate adjusted coefficient -0.11, 95% CI -0.20 — -0.02, p=0.02) and increased infarct volume growth (multivariate adjusted coefficient 0.06, 95% CI 0.03 — 0.08, p<0.001). No significant relationship was found between RDW and FIV (multivariate adjusted coefficient 0.08, 95% CI -0.01 — 0.13, p=0.08), RDW and clinical outcomes (multivariate adjusted OR 1.66, 95% CI 0.44 — 6.28, p=0.46) probably due to the small sample size.Conclusion: For patients with LAA stroke, high RDW was associated with poorer collateral flow and increased infarct volume growth, which may explain the predictive value of RDW and poor functional outcomes in acute stroke.
Abstract P558: Identification of Embolic Stroke in Patients With Large Vessel Occlusion
- Lan Hong,
- Longting Lin,
- Gang Li,
- Jianhong Yang,
- Geng Yu,
- Min Lou,
- Mark Parsons,
- Xin Cheng and
- qiang Dong
Stroke Volume 52, Issue Suppl_11 March 2021

Abstract Export Citations

Abstract
Objective: To develop a simple and objective score using clinical variables and quantified perfusion measures to identify embolic stroke with large vessel occlusions.Methods: Eligible patients from the Chinese centers participating in the International Stroke Perfusion Imaging Registry were included in this study. Patients were split into a derivation cohort (n=213) and a validation cohort (n=116). A score was developed according to the coefficients of independent predictors of embolic stroke from stepwise logistic regression model in the derivation cohort. The performance of the score was validated by assessing its discrimination and calibration. Additionally, a comparison between the area under curve (AUC) of history of atrial fibrillation (AF) alone and history of AF plus the score was also conducted.Results: The independent predictors of embolic stroke made up the Chinese Embolic Stroke Score (CHESS). There were: age (≥64 years, 1 point), non-smoking history (1 point), non-hypertension history (1 point) , baseline NIH Stroke Scale (≥14, 1 point) and delay time>6s volume/delay time>3s volume on perfusion imaging (≥0.23, 2 points). The AUC of CHESS in the derivation cohort and validation cohort were 0.80 and 0.72 respectively. Calibration tests indicated high agreement between predicted and observed probabilities. The AUC of AF-plus-CHESS compared to history of AF alone was significant (derivation cohort P<0.001; validation cohort P=0.01).Conclusions: In a Chinese population, CHESS reliably and independently identified embolic stroke as the cause of large vessel occlusion.
Letter by Zhang et al Regarding Article, “Heart Failure Stimulates Tumor Growth by Circulating Factors”
- Jian Zhang,
- Hui-yao Lan and
- Song Wan
Circulation Volume 139, Issue 529 January 2019

Export Citations PDF/EPUB

Abstract
Abstract TMP54: Persistent Penumbral Profiles Indicate a Potentially Good Outcome in Acute Stroke Patients Without Major Reperfusion
- Lan Hong,
- Longting Lin,
- Chushuang Chen,
- Andrew Bivard,
- Christopher R Levi,
- Ya Su,
- Yifeng Ling,
- Mark W Parsons,
- Xin Cheng,
- qiang Dong and
Stroke Volume 55, Issue Suppl_11 February 2024

Abstract Export Citations

Abstract
Background: It is acknowledged that penumbra can exist beyond 24 hours after stroke onset. The aim of this study was to explore the association between penumbral persistence at 24-72 hours and clinical outcomes in patients who did not achieve major reperfusion.Methods: Eligible patients participating in the International Stroke Perfusion Imaging Registry with repeated 24-72 hours perfusion imaging were included in this study. Persistent penumbra was evaluated as the volume of hypoperfusion lesion on repeated perfusion imaging divided by infarct volume on the follow-up imaging at 24-72 hours post arrival. Short-term clinical outcomes were defined as neurological deterioration at 24-72 hours and modified Rankin Scale (mRS) 0-2 at discharge. Long-term outcome was defined as mRS 0-2 at 3 months. The association between persistent penumbra and clinical outcomes was explored using multivariable-adjusted logistic regression models.Results: A total number of 203 patients were included in this study. Persistent penumbra was associated with decreased odds of neurological deterioration at 24-72 hours (multivariable-adjusted OR=0.3, P=0.01) and increased odds of mRS 0-2 at 3 months (multivariable-adjusted OR=2.7, P=0.03). Persistent penumbra was not associated with mRS 0-2 at discharge (multivariable-adjusted OR=2.5, P=0.30).Discussion: Persistent penumbra in acute stroke patients without major reperfusion was generally associated with a better clinical outcome. This evidence suggested that there were patients with persistent hemodynamic support, for whom major reperfusion might not be pivotal to achieve a good clinical outcome. How to identify these patients and what treatment strategy can be made to stabilize the hemodynamics need future investigation.
Abstract 1767: Mice Lacking Smad3 are Protected against Angiotensin II-Induced Cardiac Inflammation and Fibrosis
- Hui Y Lan,
- Xiao R Huang,
- Arthur C Chung,
- Fuye Yang,
- Li Zhou,
- Chuxia Deng,
- Hung-Fat Tse and
- Chu Pak Lau
Circulation Volume 118, Issue suppl_1828 October 2008

Abstract Export Citations

Abstract
Angiotensin II (Ang II) is a key mediator of cardiac inflammation and fibrosis in chronic heart diseases. It is known that Ang II mediates vascular fibrosis by activating TGF-β/Smad signaling in vitro. We thus hypothesized that Ang II may activate Smad3 to mediate cardiac inflammation and fibrosis. The critical role for Smad3 in Ang II-mediated cardiac inflammation and fibrosis was examined in groups of 8 Smad3 knockout (KO) and wild-type (WT) mice by subcutaneous infusion of Ang II (or saline control) at a dose of 1000ng/kg/min via osmotic minipumps for 14 days. After Ang II infusion, both Smad3 KO and WT mice developed equal levels of high blood pressure (158–161 ± 5.4 mmHg vs saline control 100 –112 ± 2.6 mmHg, p < 0.001). However, cardiac inflammation and fibrosis were developed in Smad3 WT, but not in Smad3 KO mice. Real-time PCR and immunohistochemistry demonstrated that there was a 10 –20 fold increase in cardiac inflammation (including IL-1β, TNFα, MCP-1, ICAM-1, macrophage and T cell infiltration) and fibrosis (collagen I, III, α-SMA) in Smad3 WT mice (all p < 0.01), which was abrogated in Smad3 KO mice (all p < 0.01). Further studies revealed that prevention of Ang II-induced cardiac inflammation and fibrosis in Smad3 KO mice was associated with inhibition of cardiac TGF-β 1 and CTGF, a loss of Smad3 signaling, and inactivation of the NF.β B/p65 pathway (all p < 0.01). These findings were further confirmed in Smad3 WT and KO cardiac fibroblasts in vitro. Western blot and real-time PCR demonstrated that loss of Smad3 prevented Ang II-induced inflammation and fibrosis in primary culture of cardiac fibroblasts. Smad3 plays an essential role in cardiac inflammation and fibrosis in response to Ang II, which suggests that targeting Smad3 signaling may represent a novel therapeutic strategy for chronic cardiovascular diseases.
Abstract 5: Malignant Venous Outflow Profile Predicts Futile Recanalization After Endovascular Thrombectomy.
- Siyuan Li,
- Lan Hong,
- Yiran Zhang,
- Xinyu Liu and
- Xin Cheng
Stroke Volume 54, Issue Suppl_11 February 2023

Abstract Export Citations

Abstract
Objective: To explore the association of baseline venous outflow from the occluded cerebral territory and futile recanalization (FR) in patients with acute ischemic stroke due to large vessel occlusion (LVO) in the anterior circulation.Methods: Consecutive patients from a prospectively maintained stroke database were included in this study if they presented with a multimodal CT-confirmed LVO in the anterior circulation and underwent thrombectomy within 24 hours after stroke onset. Excellent recanalization of the occluded artery, defined as final mTICI 2c-3 on digital subtraction angiography, was considered to be futile if patients fail to achieve functional independence (modified Rankin Scale of 0-2) at 90 days. Baseline venous outflow profile was determined by a 7-point semi-quantitative scoring system which assessed ipsilateral venous opacification of the vein of Labbe, Trolard and superficial middle cerebral vein on single-phase CTA source images. Hypoperfusion intensity ratio (HIR, defined as delay time >6 seconds/delay time >3 seconds) was applied to evaluate tissue-level collateral status.Results: 145 patients met the inclusion criteria. Multivariable logistic regression analysis showed that malignant venous outflow (OR 4.30 [95% CI 1.41-14.57]; p =0.013) was independently associated with functional dependence regardless of age, glucose, HIR, early neurologic deterioration, hemorrhagic transformation and final infarct volume. FR was observed in 24/52 (46%) recanalized patients. Stepwise logistic regression revealed a poor venous outflow profile at presentation as an independent predictor of FR (OR 7.04 [95% CI 1.29-50.16]; p =0.03) adjusted for baseline NIH Stroke Scale score, HIR and presence of hemorrhagic transformation.Conclusion: A malignant venous outflow profile at baseline is associated with FR in patients with LVO. The mechanism by which poor venous outflow from the occluded territory hinders clinical recovery despite prompt successful thrombectomy remains to be determined.
Endothelial GNAQ p.R183Q Increases ANGPT2 (Angiopoietin-2) and Drives Formation of Enlarged Blood Vessels
- Lan Huang,
- Colette Bichsel,
- Alexis L. Norris,
- Jeremy Thorpe,
- Jonathan Pevsner,
- Sanda Alexandrescu,
- Anna Pinto,
- David Zurakowski,
- Robin J. Kleiman,
- Mustafa Sahin,
- Arin K. Greene and
- Joyce Bischoff
Arteriosclerosis, Thrombosis, and Vascular Biology Volume 42, Issue 11 January 2022

Abstract Export Citations PDF/EPUB

Abstract
Objective:Capillary malformation (CM) occurs sporadically and is associated with Sturge-Weber syndrome. The somatic mosaic mutation in GNAQ (c.548G>A, p.R183Q) is enriched in endothelial cells (ECs) in skin CM and Sturge-Weber syndrome brain CM. Our goal was to investigate how the mutant Gαq (G-protein αq subunit) alters EC signaling and disrupts capillary morphogenesis.Approach and Results:We used lentiviral constructs to express p.R183Q or wild-type GNAQ in normal human endothelial colony forming cells (EC-R183Q and EC-WT, respectively). EC-R183Q constitutively activated PLC (phospholipase C) β3, a downstream effector of Gαq. Activated PLCβ3 was also detected in human CM tissue sections. Bulk RNA sequencing analyses of mutant versus wild-type EC indicated constitutive activation of PKC (protein kinase C), NF-κB (nuclear factor kappa B) and calcineurin signaling in EC-R183Q. Increased expression of downstream targets in these pathways, ANGPT2 (angiopoietin-2) and DSCR (Down syndrome critical region protein) 1.4 were confirmed by quantitative PCR and immunostaining of human CM tissue sections. The Gαq inhibitor YM-254890 as well as siRNA targeted to PLCβ3 reduced mRNA expression levels of these targets in EC-R183Q while the pan-PKC inhibitor AEB071 reduced ANGPT2 but not DSCR1.4. EC-R183Q formed enlarged blood vessels in mice, reminiscent of those found in human CM. shRNA knockdown of ANGPT2 in EC-R183Q normalized the enlarged vessels to sizes comparable those formed by EC-WT.Conclusions:Gαq-R183Q, when expressed in ECs, establishes constitutively active PLCβ3 signaling that leads to increased ANGPT2 and a proangiogenic, proinflammatory phenotype. EC-R183Q are sufficient to form enlarged CM-like vessels in mice, and suppression of ANGPT2 prevents the enlargement. Our study provides the first evidence that endothelial Gαq-R183Q is causative for CM and identifies ANGPT2 as a contributor to CM vascular phenotype.Graphical Abstract
Angiotensin II Induces Connective Tissue Growth Factor and Collagen I Expression via Transforming Growth Factor–β–Dependent and –Independent Smad Pathways: The Role of Smad3
- Fuye Yang,
- Arthur C.K. Chung,
- Xiao Ru Huang and
- Hui Yao Lan
Hypertension Volume 54, Issue 41 October 2009

Abstract Export Citations PDF/EPUB

Abstract
Connective tissue growth factor (CTGF) plays a critical role in angiotensin II (Ang II)–mediated hypertensive nephropathy. The present study investigated the mechanisms and specific roles of individual Smads in Ang II–induced CTGF and collagen I expression in tubular epithelial cells with deletion of transforming growth factor (TGF)-β1, overexpression of Smad7, or knockdown of Smad2 or Smad3. We found that Ang II–induced tubular CTGF and collagen I mRNA and protein expressions were regulated positively by phosphorylated Smad2/3 but negatively by Smad7 because overexpression of Smad7-abolished Ang II–induced Smad2/3 phosphorylation and upregulation of CTGF and collagen I in vitro and in a rat model of remnant kidney disease. Additional studies revealed that, in addition to a late (24-hour) TGF-β–dependent Smad2/3 activation, Ang II also induced a rapid activation of Smad2/3 at 15 minutes and expression of CTGF and collagen I in tubular epithelial cells lacking the TGF-β gene, which was blocked by the addition of an Ang II type 1 receptor antagonist (losartan) and inhibitors to extracellular signal–regulated kinase 1/2 (PD98059) and p38 (SB203580) but not by inhibitors to Ang II type 2 receptor (PD123319) or c-Jun N-terminal kinase (SP600125), demonstrating a TGF-β–independent, Ang II type 1 receptor–mediated extracellular signal–regulated kinase/p38 mitogen-activated protein kinase cross-talk pathway in Ang II–mediated CTGF and collagen I expression. Importantly, the ability of knockdown of Smad3, but not Smad2, to inhibit Ang II–induced CTGF and collagen I expression further revealed an essential role for Smad3 in Ang II–mediated renal fibrosis. In conclusion, Ang II induces tubular CTGF expression and renal fibrosis via the TGF-β–dependent and –independent Smad3 signaling pathways, suggesting that targeting Smad3 may have therapeutic potential for hypertensive nephropathy.
Abstract WP91: Cerebral Small Vessel Disease Burden Predicts Poor Collateral Flow in Acute Ischemic Stroke Patients With Large Artery Atherosclerosis
- Yueming Wang,
- Lumeng Yang,
- Lan Hong,
- Longting Lin,
- Mark Parsons,
- Xin Cheng and
- Qiang Dong
Stroke Volume 51, Issue Suppl_1

Abstract Export Citations

Abstract
Aim: We sought to determine whether the extent of chronic white matter hyper-intensities (WMH) and white matter hypo-perfusion (WMHP), as markers of cerebral small vessel disease (CSVD), were associated with poor collateral flow in acute ischemic stroke as a potential cause of unfavorable functional outcome.Methods: Acute ischemic stroke patients within 12 hours of symptom onset with complete baseline and follow-up clinical data, who: (1) had large vessel occlusion in anterior circulation, (2) underwent baseline perfusion CT (CTP), (3) had 24-hour MRI were prospectively recruited. The volume of WMH was measured in the unaffected hemisphere on MRI semi-automatically. WMHP was measured as Delay Time (DT)>2s in white matter of unaffected hemisphere on CTP. Quality of Collateral flow was defined by the volume ratio of DT>3s/DT>6s on CTP. Unfavorable functional outcome was 90-day modified Rankin Scale (mRS)>2. The association between volumes of WMH, WMHP, and collateral flow were evaluated using univariate and multivariate generalized linear models. We also assessed the relationship between WMH, WHMP, and functional outcome with logistic regression.Results: There were 96 (66.6±12.81 years old, 35 female) ischemic stroke patients, and 51 were due to large artery atherosclerosis (LAA). In all patients, after multivariate adjustment, WMH volume (5.6±7.11ml) did not correlate with collateral flow (coefficient -0.01, 95% CI -0.03 to 0, P=0.09), although it was marginally associated with unfavorable outcome (Odds Ratio: 1.08, p=0.06, 95% CI 1 to 1.17). In all patients, WMHP volume (8.6±8.54ml) did not correlate with collateral flow (coefficient -0.01, 95% CI -0.01 to 0, P=0.29). However, in the LAA subgroup, WMH volume was strongly related to poorer collateral flow, i.e. lower DT>3s/DT>6s ratio(coefficient -0.03, 95% CI -0.04 to -0.01, P=0.01). WMHP volume was also correlated with poor collateral flow (coefficient -0.01, 95% CI -0.02 to 0, P=0.02).Conclusion: CSVD may contribute to poor collateral flow in acute stroke, especially in patients with LAA. This potentially explains the association between CSVD and poor acute stroke outcomes.
Deletion of Angiotensin-Converting Enzyme-2 Promotes Hypertensive Nephropathy by Targeting Smad7 for Ubiquitin Degradation
- Zhen Liu,
- Xiao-Ru Huang,
- Hai-Yong Chen,
- Erik Fung,
- Jian Liu and
- Hui-Yao Lan
Hypertension Volume 70, Issue 41 October 2017

Abstract Export Citations PDF/EPUB

Abstract
Angiotensin-converting enzyme-2 (ACE2) is downregulated in hypertensive nephropathy. The present study investigated the mechanisms whereby loss of ACE2 promoted angiotensin II–induced hypertensive nephropathy in ACE2 gene knockout mice. We found that compared with wild-type animals, mice lacking ACE2 developed much more severe hypertensive nephropathy in response to chronic angiotensin II infusion, including higher levels of blood pressure, urinary protein excretion, serum creatinine, and progressive renal fibrosis and inflammation. Mechanistic studies revealed that worsening kidney injury in ACE2 knockout mice was associated with an increase in Smurf2 (Smad-specific E3 ubiquitin protein ligase 2), a decrease in renal Smad7, and marked activation of TGF-β (transforming growth factor β)/Smad3 and NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling, suggesting that Smurf2-dependent Smad7 ubiquitin degradation may be a key mechanism whereby loss of ACE2 promotes angiotensin II–induced TGF-β/Smad3 and NF-κB–mediated hypertensive nephropathy. This was validated by restoring Smad7 locally in the kidneys of ACE2 knockout mice to block angiotensin II–induced TGF-β/Smad3-mediated renal fibrosis and NF-κB–driven renal inflammation. Moreover, we found that angiotensin II could induce microRNA-21 in the mouse kidney and in cultured mesangial cells via a Smad3-dependent mechanism, which was enhanced by deleting ACE2 but inhibited by overexpressing renal Smad7. In conclusion, loss of ACE2 promotes angiotensin II–induced renal injury by targeting Smad7 for degradation via a Smurf2-dependent mechanism. Overexpression of renal Smad7 protects against hypertensive nephropathy by inactivating angiotensin II–induced TGF-β/Smad3 and NF-κB pathways and by targeting the Smad3-dependent microRNA-21 axis.
Abstract 17912: Deficiency of Smad7 Enhances Myocardial Remodeling Induced by Angiotensin II
- Li Hua Wei,
- Xiao Ru Huang,
- Yang Zhang,
- Rainer Heuchel,
- Cheuk-Man Yu and
- Hui Yao Lan
Circulation Volume 126, Issue suppl_2120 November 2012

Abstract Export Citations

Abstract
Purpose: Smad7 is a critical negative regulator of TGF-β/Smad and NF-κB signaling. We have previously shown that disruption of Smad7 function accelerates fibrosis and inflammation in obstructed kidney disease and over expression of Smad7 inhibits fibrosis and inflammation in diabetic kidney injury. However, the protective mechanism of Smad7 in myocardial remodeling remains unclear. Therefore, the present study aimed to investigate the role of Smad7 in cardiac remodeling induced by angiotensin II infusion. Methods: Hypertensive cardiopathy was induced in both Smad7 knockout (KO) and wild-type (WT) mice by subcutaneous infusion of Ang II (1.46mg/kg/day) for 28 days. Blood pressure was measured by the tail-cuff method; cardiac function was detected by echocardiography. Cardiac fibrosis and inflammation were examined by real-time PCR, western blotting and immunohistochemistry. Results: Although equal levels of high blood pressure were developed in both Smad7 KO and WT mice, Smad7 KO mice developed more severe cardiac injury as demonstrated by impaired cardiac function including a significant increase in left ventricular (LV) mass (P<0.01) and reduction of LV ejection fraction (P<0.001). Real-time PCR, western blot and immunohistochemistry detected that deletion of Smad7 significantly enhanced Ang II-induced cardiac fibrosis and inflammation, including upregulation of collagen I, α-SMA, proinflammatory cytokines (interleukin-1β, tumor necrosis factor-α), and CD3⁺ T cells and F4/80⁺ macrophages (all p<0.05, compared to Smad7 WT mice respectively). These changes were associated with enhanced activation of TGF-β /Smad and NF-κB signaling pathways. Conclusion: Deficiency of Smad7 enhances fibrosis and inflammation in Ang II-induced hypertensive cardiac remodeling by enhancing activation of TGF-β/Smad and NF-κB signaling pathways. Results from this study reveal that Smad7 plays a protective role in AngII-mediated hypertensive cardiac remodeling and suggest that Smad7 may be a novel therapeutic agent for hypertensive cardiovascular disease.
Knockdown of Cytochrome P450 2E1 Inhibits Oxidative Stress and Apoptosis in the cTnT^R141W Dilated Cardiomyopathy Transgenic Mice
- Dan Lu,
- Yuanwu Ma,
- Wei Zhang,
- Dan Bao,
- Wei Dong,
- Hong Lian,
- Lan Huang and
- Lianfeng Zhang
Hypertension Volume 60, Issue 11 July 2012

Abstract Export Citations PDF/EPUB

Abstract
Cytochrome P450 2E1 (CYP2E1) is a cytochrome P450 enzyme that catalyzes the metabolism of toxic substrates. CYP2E1 is upregulated in heart disease, including the dilated cardiomyopathy (DCM) mouse model. Here, knockdown of CYP2E1 significantly ameliorated the dilated left ventricle, thin wall, and dysfunctional contraction in the cTnT^R141W and adriamycin-induced DCM mouse models. Interstitial fibrosis, poorly organized myofibrils, and swollen mitochondria with loss of cristae were improved in the myocardium of α-myosin heavy chain (MHC)-cTnT^R141W×CYP2E1-silence double-transgenic mice when compared with the cTnT^R141W transgenic mice. Oxidative stress, the activation of caspase 3 and caspase 9, the release of cytochrome c, and the apoptosis in the myocardium were significantly decreased in double-transgenic mice compared with the cTnT^R141W transgenic mice. In summary, the expression of CYP2E1 is upregulated in heart disease and might be induced by hypoxemia in cardiomyopathy. The overexpression of CYP2E1 can enhance the metabolism of endogenous ketones to meet the energy demand of the heart in certain disease states, but the overexpression of CYP2E1 can also increase oxidative stress and apoptosis in the DCM heart. Knockdown or downregulation of CYP2E1 might be a therapeutic strategy to control the development of DCM after mutations of cTnT^R141W or other factors, because DCM is the third most common cause of heart failure and the most frequent cause of heart transplantation.
Advanced Glycation End Products Activate a Chymase-Dependent Angiotensin II–Generating Pathway in Diabetic Complications
- Vijay Koka,
- Wansheng Wang,
- Xiao Ru Huang,
- Shokei Kim-Mitsuyama,
- Luan D. Truong and
- Hui Y. Lan
Circulation Volume 113, Issue 1014 March 2006

Abstract Export Citations PDF/EPUB

Abstract
Background— Angiotensin II is a key mediator of diabetes-related vascular disease. It is now recognized that in addition to angiotensin-converting enzyme, chymase is an important alternative angiotensin II–generating enzyme in hypertension and diabetes. However, the mechanism of induction of chymase in diabetes remains unknown.Methods and Results— Here, we report that chymase is upregulated in coronary and renal arteries in patients with diabetes by immunohistochemistry. Upregulation of vascular chymase is associated with deposition of advanced glycation end products (AGEs), an increase in expression of the receptor for AGEs (RAGE), and activation of ERK1/2 MAP kinase. In vitro, AGEs can induce chymase expression and chymase-dependent angiotensin II generation in human vascular smooth muscle cells via the RAGE-ERK1/2 MAP kinase–dependent mechanism. This is confirmed by blockade of AGE-induced vascular chymase expression with a neutralizing RAGE antibody and an inhibitor to ERK1/2 and by overexpression of the dominant negative ERK1/2. Compared with angiotensin-converting enzyme, chymase contributes to the majority of angiotensin II production (>70%, P<0.01) in response to AGEs. Furthermore, AGE-induced angiotensin II production is blocked by the anti-RAGE antibody and by inhibition of ERK1/2 MAP kinase activities.Conclusions— AGEs, a hallmark of diabetes, induce chymase via the RAGE-ERK1/2 MAP kinase pathway. Chymase initiates an important alternative angiotensin II–generating pathway in diabetes and may play a critical role in diabetic vascular disease.
Endothelium-Derived Nitric Oxide Modulates Vascular Action of Aldosterone in Renal Arteriole
- Shuji Arima,
- Kentaro Kohagura,
- Hong-Lan Xu,
- Akira Sugawara,
- Akira Uruno,
- Fumitoshi Satoh,
- Kazuhisa Takeuchi and
- Sadayoshi Ito
Hypertension Volume 43, Issue 21 February 2004

Abstract Export Citations PDF/EPUB

Abstract
We have recently demonstrated that aldosterone causes nongenomic vasoconstriction by activating phospholipase C (PLC) in the preglomerular afferent arteriole (Af-Art). In the present study, we tested the hypothesis that endothelium modulates this vasoconstrictor action by releasing nitric oxide (NO). In addition, to study the post-PLC mechanism, we examined possible contributions of phosphoinositol hydrolysis products. Rabbit Af-Arts were microperfused at 60 mm Hg in vitro, and increasing doses of aldosterone (10⁻¹⁰ to 10⁻⁸ mol/L) were added to the bath and lumen. Aldosterone caused dose-dependent vasoconstriction (within 10 minutes); significant (P<0.01) constriction was observed from 5×10⁻⁹ mol/L, and at 10⁻⁸ mol/L, intraluminal diameter decreased by 29%±3% (n=9). Disrupting the endothelium augmented vasoconstriction; significant constriction was observed from 10⁻¹⁰ mol/L, and at 10⁻⁸ mol/L, the diameter decreased by 38%±2% (n=6). NO synthesis inhibition reproduced this augmentation (n=7). Pretreatment with chelerythrine (10⁻⁶ mol/L), a protein kinase C (PKC) inhibitor, slightly attenuated the constriction; aldosterone at 10⁻⁸ mol/L now decreased the diameter by 18%±3% (n=7). However, in Af-Arts treated with thapsigargin (10⁻⁶ mol/L) or dantrolene (3×10⁻⁵ mol/L), which blocks inositol 1,4,5-triphosphate (IP₃)-induced intracellular calcium release, aldosterone at 10⁻⁸ mol/L decreased the diameter by only 9%±1% (n=6) or 9%±2% (n=5), respectively. These results demonstrate that in the Af-Art endothelium-derived NO modulates vasoconstrictor actions of aldosterone that are mediated by the activation of both IP₃ and PKC pathways. Such vasoconstrictor actions of aldosterone may contribute to the development or aggravation of hypertension by elevating renal vascular resistance in cardiovascular diseases associated with endothelium dysfunction.
Uric Acid, Hominoid Evolution, and the Pathogenesis of Salt-Sensitivity
- Susumu Watanabe,
- Duk-Hee Kang,
- Lili Feng,
- Takahiko Nakagawa,
- John Kanellis,
- Hui Lan,
- Marilda Mazzali and
- Richard J. Johnson
Hypertension Volume 40, Issue 31 September 2002

Abstract Export Citations PDF/EPUB

Abstract
Humans have elevated serum uric acid as a result of a mutation in the urate oxidase (uricase) gene that occurred during the Miocene. We hypothesize that the mutation provided a survival advantage because of the ability of hyperuricemia to maintain blood pressure under low-salt dietary conditions, such as prevailed during that period. Mild hyperuricemia in rats acutely increases blood pressure by a renin-dependent mechanism that is most manifest under low-salt dietary conditions. Chronic hyperuricemia also causes salt sensitivity, in part by inducing preglomerular vascular disease. The vascular disease is mediated in part by uric acid-induced smooth muscle cell proliferation with activation of mitogen-activated protein kinases and stimulation of cyclooxygenase-2 and platelet-derived growth factor. Although it provided a survival advantage to early hominoids, hyperuricemia may have a major role in the current cardiovascular disease epidemic.
De Novo Expression of Macrophage Migration Inhibitory Factor in Atherogenesis in Rabbits
- Shu-Guang Lin,
- Xi-Yong Yu,
- Yong-Xiong Chen,
- Xiao R. Huang,
- Christine Metz,
- Richard Bucala,
- Chu-Pak Lau and
- Hui Y. Lan
Circulation Research Volume 87, Issue 128 December 2000

Abstract Export Citations PDF/EPUB

Abstract
Abstract—Macrophage migration inhibitory factor (MIF) has been shown to play an important role in macrophage-mediated diseases. We investigate the potential role of MIF in atherogenesis using a hypercholesterolemic rabbit model. New Zealand White rabbits fed with a 2% cholesterol diet developed hypercholesterolemia and early fatty streaks at 1 month. The lesions became advanced at 3 months and were associated with de novo MIF expression by vascular endothelial cells (VECs) and smooth muscle cells (SMCs), as demonstrated by immunohistochemistry, reverse transcriptase–polymerase chain reaction, and in situ hybridization. By contrast, there was no increase in MIF levels in rabbits fed a normal diet. In early atherogenesis, marked upregulation of MIF mRNA and protein by VECs and some intimal cells were closely associated with CD68⁺ monocyte adhesion onto and subsequent migration into subendothelial space. Of significance, the accumulation of macrophages was exclusively localized to areas of strong MIF expression, which may be associated with the macrophage-rich fatty streak lesion formation. Upregulation of MIF by SMCs is transient during atherogenesis. Importantly, strong MIF expression by activated macrophages may be responsible for the development of foam cell-rich lesions. Finally, the ability of MIF to induce intercellular adhesion molecule-1 expression by VECs implicates its pathogenic role in atherogenesis. In conclusion, the present study provides the first demonstration that MIF is markedly upregulated during atherogenesis. Upregulation of MIF by VECs and SMCs may play a role in macrophage adhesion, transendothelial migration, accumulation, and, importantly, transformation into foam cells. Furthermore, strong MIF expression by macrophages may both initiate and amplify the atherogenesis process.
Smad3 Mediates Cardiac Inflammation and Fibrosis in Angiotensin II–Induced Hypertensive Cardiac Remodeling
- Xiao R. Huang,
- Arthur C.K. Chung,
- Fuye Yang,
- Wensheng Yue,
- Chuxia Deng,
- Chu Pak Lau,
- Hung Fat Tse and
- Hui Y. Lan
Hypertension Volume 55, Issue 51 May 2010

Abstract Export Citations PDF/EPUB

Abstract
Although Smad3 is a key mediator of fibrosis, the functional role of Smad3 in hypertensive cardiovascular disease remains unclear. The present study tested the hypothesis that angiotensin II may activate the transforming growth factor-β/Smad3 pathway to mediate hypertensive cardiac remodeling in Smad3 knockout (KO) and wild-type mice by subcutaneous angiotensin II infusion and in the primary culture of Smad3 KO cardiac fibroblasts. Fourteen days after angiotensin II infusion, both Smad3 KO and wild-type mice developed equal levels of high blood pressure. However, hypertensive cardiac fibrosis and inflammation were developed in Smad3 wild-type but not in Smad3 KO mice. This was demonstrated by the findings that mice lacking Smad3 were protected against a fall in left ventricular ejection fraction (P<0.05), an increase in left ventricular mass (P<0.05), and the development of cardiac fibrosis and inflammation, including upregulation of transforming growth factor-β1, connective tissue growth factor, collagen I/III, α-smooth muscle actin, interleukin 1β, tumor necrosis factor-α, monocyte chemoattractant protein 1, intercellular adhesion molecule 1, and an increase in macrophage and T-cell infiltration in left ventricular tissues (all P<0.01, respectively). Additional studies in vitro also revealed that angiotensin II–induced cardiac fibrosis and inflammation were prevented in Smad3 KO cardiac fibroblasts. Inactivation of both Smad3 and nuclear factor κB/p65 signaling pathways was a key mechanism by which Smad3 KO mice were protected from angiotensin II–mediated hypertensive cardiac remodeling. In conclusion, Smad3 plays an essential role in hypertensive cardiac remodeling. Results from this study suggest that targeting Smad3 may be a novel therapeutic strategy for hypertensive cardiovascular disease.

Search

Narrow Results

Journal Title

Article Type

Subject

Date Range

Author

Export Citation

Advanced

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract