Selective inhibition of protein kinase C beta(2) attenuates inducible nitric oxide synthase-mediated cardiovascular abnormalities in streptozotocin-induced diabetic rats.

Abstract

OBJECTIVE:

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.

RESEARCH DESIGN AND METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Prabhakara Reddy Nagareddy, Hesham Soliman, Guorong Lin, Padmesh S Rajput, Ujendra Kumar, John H McNeill, Kathleen M MacLeod
• Journal: Diabetes (Diabetes) Vol. 58 Issue 10 Pg. 2355-64 (Oct 2009) ISSN: 1939-327X [Electronic] United States
• PMID: 19587355 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Enzyme Inhibitors
• Indoles
• Maleimides
• N(6)-(1-iminoethyl)lysine
• Mannitol
• ruboxistaurin
• Nitric Oxide Synthase Type II
• Protein Kinase C
• Protein Kinase C beta
• Glucose
• Lysine

Topics

• Animals
• Aorta (enzymology)
• Blood Glucose (metabolism)
• Cardiovascular Diseases (prevention & control)
• Cells, Cultured
• Diabetes Mellitus, Experimental (enzymology)
• Diabetic Angiopathies (prevention & control)
• Enzyme Induction
• Enzyme Inhibitors (pharmacology)
• Glucose (pharmacology)
• Indoles (pharmacology)
• Lysine (analogs & derivatives, pharmacology)
• Male
• Maleimides (pharmacology)
• Mannitol (pharmacology)
• Muscle, Smooth, Vascular (enzymology)
• Myocytes, Cardiac (cytology, enzymology)
• Nitric Oxide Synthase Type II (antagonists & inhibitors, biosynthesis, metabolism)
• Protein Kinase C (antagonists & inhibitors)
• Protein Kinase C beta
• Rats
• Rats, Wistar