PKC-ε-dependent survival signals in diabetic hearts

Abstract

Diabetes mellitus is complicated by the development of a primary cardiomyopathy, which contributes to the excess morbidity and mortality of this disorder. The protein kinase C (PKC) family of isozymes plays a key role in the cardiac phenotype expressed during postnatal development and in response to pathological stimuli. Hyperglycemia is an activating signal for cardiac PKC isozymes that modulate a myriad of cell events including cell death and survival. The ε-isozyme of the PKC family transmits a powerful survival signal in cardiac muscle cells. Accordingly, to test the hypothesis that endogenous activation of cardiac PKC-ε will protect against hyperglycemic cell injury and left ventricular dysfunction, diabetes mellitus was induced using streptozotocin in genetically engineered mice with cardiac-specific expression of the PKC-ε translocation activator [ψε-receptors for activated C kinase (ψε-RACK)]. The results demonstrate a striking PKC-ε cardioprotective phenotype in diabetic ψε-RACK (ε-agonist) mice that is characterized by inhibition of the hyperglycemia apoptosis signal, attenuation of hyperglycemia-mediated oxidative stress, and preservation of parameters of left ventricular pump function. Hearts of diabetic ε-agonist mice exhibited selective trafficking of PKC-ε to membrane and mitochondrial compartments, phosphorylation/inactivation of the mitochondrial Bad protein, and inhibition of cytochrome c release. We conclude that activation of endogenous PKC-ε in hearts of diabetic ε-agonist mice promotes the survival phenotype, attenuates markers of oxidative stress, and inhibits the negative inotropic properties of chronic hyperglycemia.

Inhibition of wild-type p66ShcA in mesangial cells prevents glycooxidant-dependent FOXO3a regulation and promotes the survival phenotype

“…At the cellular level, recent work has linked ROS to induction of the apoptotic program in visceral epithelial cells (podocytes) of Akita and db/db genetic models of diabetes mellitus (31), an event that precedes the onset of proteinuria (31). These results confirm earlier work in mesangial cells (12,13,39) along with cardiac myocytes (11,20), neurons (30), and retinal pericytes (8), indicating that oxidant-induced apoptosis may account for significant rates of cell death in kidney and other organ systems in diabetes. The application of a gene-based strategy to inhibit apoptosis, attenuate or prevent pathological remodeling, and preserve organ function (21) may represent an exciting new avenue for therapeutic intervention in the kidney.…”

A Protein Kinase Cε-Anti-apoptotic Kinase Signaling Complex Protects Human Vascular Endothelial Cells against Apoptosis through Induction of Bcl-2

“…In vivo models have demonstrated a key role for PKC⑀ in ischemic pre-conditioning (31,32,49,69) and resistance to oxidative stress (68,70). Our data suggest that PKC⑀, through its interaction with Akt and induction of Bcl-2, plays another important role in vascular cytoprotection by contributing to the maintenance of endothelial homeostasis and vascular integrity.…”

Protein kinase C subtypes and retinal ischemic preconditioning

“…Paradoxically, PKCδ activation has been associated with apoptosis in neutrophils via capase-3 activation (Pongracz et al, 1999) and in vivo after rat brain ischemia and reperfusion (Bright et al, 2004). Activation of PKCε has been associated with protection from apoptosis in myocardium and in glioma cells, in part by activation of the survival factor protein kinase B (Akt) (Malhotra et al, 2005;Okhrimenko et al, 2005;Tanaka et al, 2004). Our experiments tested the hypothesis that PKC-δ and -ε are integral components in retinal IPC protection from ischemic damage and in IPC-mimicking that is induced by the opening of mKATP channels.…”