title: PKC-{epsilon}-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 epsilon-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-epsilon 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-epsilon translocation activator [psiepsilon-receptors for activated C kinase (psiepsilon-RACK)]. The results demonstrate a striking PKC-epsilon cardioprotective phenotype in diabetic psiepsilon-RACK (epsilon-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 epsilon-agonist mice exhibited selective trafficking of PKC-epsilon 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-epsilon in hearts of diabetic epsilon-agonist mice promotes the survival phenotype, attenuates markers of oxidative stress, and inhibits the negative inotropic properties of chronic hyperglycemia.
authors.affiliation: Division of Nephrology, Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103, USA. Malhotas@umdnj.edu
authors.forename: Ashwani
authors.initials: A
authors.lastname: Malhotra
authors.forename: Rebecca
authors.initials: R
authors.lastname: Begley
authors.forename: Barinder P S
authors.initials: BP
authors.lastname: Kang
authors.forename: Irmindra
authors.initials: I
authors.lastname: Rana
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Guiping
authors.initials: G
authors.lastname: Yang
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Meggs
mesh_terms: D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D015398:Signal Transduction / Q000502:physiology*; D016277:Ventricular Function, Left
chemical_list: D045304:Cytochromes c; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D048049:Extracellular Signal-Regulated MAP Kinases