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: Ashwani Malhotra, Rebecca Begley, Barinder P S Kang, Irmindra Rana, Jing Liu, Guiping Yang, Daria Mochly-Rosen, Leonard G Meggs
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 289 Issue 4 Pg. H1343-50 (Oct 2005) ISSN: 0363-6135 [Print] United States
• PMID: 15894568 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cytochromes c
• Prkce protein, mouse
• Protein Kinase C
• Protein Kinase C-epsilon
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Apoptosis
• Cardiomyopathies (etiology, metabolism, pathology)
• Cytochromes c (metabolism)
• Diabetes Mellitus, Experimental (complications, metabolism, pathology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Hyperglycemia (metabolism, pathology)
• Mice
• Mice, Mutant Strains
• Myocardium (enzymology, pathology)
• Oxidative Stress (physiology)
• Phosphorylation
• Protein Kinase C (genetics, metabolism)
• Protein Kinase C-epsilon
• Signal Transduction (physiology)
• Ventricular Function, Left