Divergent Effects of PKC (Protein Kinase C) α in the Human and Animal Heart?
Therapeutic Implications for PKC Inhibitors in Cardiac Patients
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See Article by Hu et al
The PKC (protein kinase C) family consists of ≈13 members within 3 classes. PKCα belongs to the conventional/classical class of PKCs, together with PKCβ1, PKCβ2, and PKCγ. The conventional PKCs are Ca2+ and lipid activated and function downstream of Gq protein-coupled receptor signaling, which, when over activated, causes pathological cardiac remodeling and heart failure.1 PKCα and PKCβ1/II have been identified in the rodent and human heart, and PKCα expression or activity have been reported to increase in the diseased heart.1 Studies in PKCα genetic mouse models, and preclinical studies with PKC inhibitors in rodents and large animal models, have consistently suggested that inhibiting PKCα in the failing heart would be beneficial.2–9 The PKC inhibitors used have not been specific for PKCα alone (eg, ruboxistaurin, Ro-32–0432, and Ro-31–8220 inhibit PKCα/β/γ). However, PKCα is the most abundant isoform in mouse heart (based on protein content)10 and ruboxistaurin was shown to provide benefit in PKCβ/γ−/− mice subjected to pressure overload, the beneficial effects of these inhibitors has been attributed to inhibition of PKCα.2 The development of PKC-specific inhibitors has been of interest for several diseases, including those of cardiac pathogenesis (heart failure and atherosclerosis). However, to date, results from clinical trials have been disappointing.1
In the current issue of Circulation: Genomic and Precision Medicine, Hu et al11 undertook a study to ascertain the effects of reduced PKCα abundance in human left ventricle (LV) tissue. This was of interest because although animal studies had convincingly shown that inhibition of PKCα provided cardiac protection, the impact on the human heart was not clear. The identification of …