Selective Inhibition of Protein Kinase C [beta]^sub 2^ Attenuates Inducible Nitric Oxide Synthase-Mediated Cardiovascular Abnormalities in Streptozotocin-Induced Diabetic Rats

• Published in: Diabetes (New York, N.Y.) Vol. 58; no. 10; p. 2355
• Main Authors: Nagareddy, Prabhakara Reddy, Soliman, Hesham, Lin, Guorong, Rajput, Padmesh S, Kumar, Ujendra, McNeill, John H, MacLeod, Kathleen M
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 01.10.2009
• Subjects: Cardiomyocytes; Diabetes; Glucose; Heart rate; Hemodynamics; Hyperglycemia; Kinases; Nitric oxide; Oxidative stress; Proteins; Research design; Smooth muscle; Veins & arteries
• ISSN: 0012-1797; 1939-327X

Impaired cardiovascular function in diabetes is partially attributed to pathological overexpression of inducible nitric oxide synthase (iNOS) in cardiovascular tissues. We examined whether the hyperglycemia-induced increased expression of iNOS is protein kinase C-beta(2) (PKCbeta(2)) dependent and whether selective inhibition of PKCbeta reduces iNOS expression and corrects abnormal hemodynamic function in streptozotocin (STZ)-induced diabetic rats. Cardiomyocytes and aortic vascular smooth muscle cells (VSMC) from nondiabetic rats were cultured in low (5.5 mmol/l) or high (25 mmol/l) glucose or mannitol (19.5 mmol/l mannitol + 5.5 mmol/l glucose) conditions in the presence of a selective PKCbeta inhibitor, LY333531 (20 nmol/l). Further, the in vivo effects of PKCbeta inhibition on iNOS-mediated cardiovascular abnormalities were tested in STZ-induced diabetic rats. Exposure of cardiomyocytes to high glucose activated PKCbeta(2) and increased iNOS expression that was prevented by LY333531. Similarly, treatment of VSMC with LY333531 prevented high glucose-induced activation of nuclear factor kappaB, extracellular signal-related kinase, and iNOS overexpression. Suppression of PKCbeta(2) expression by small interference RNA decreased high-glucose-induced nuclear factor kappaB and extracellular signal-related kinase activation and iNOS expression in VSMC. Administration of LY333531 (1 mg/kg/day) decreased iNOS expression and formation of peroxynitrite in the heart and superior mesenteric arteries and corrected the cardiovascular abnormalities in STZ-induced diabetic rats, an action that was also observed with a selective iNOS inhibitor, L-NIL. Collectively, these results suggest that inhibition of PKCbeta(2) may be a useful approach for correcting abnormal hemodynamics in diabetes by preventing iNOS mediated nitrosative stress.