Role of inducible nitric oxide synthase in induction of RhoA expression in hearts from diabetic rats

Aims Recent studies from our laboratory demonstrated that increased expression of the small GTP-binding protein RhoA and activation of the RhoA/rho kinase (ROCK) pathway play an important role in the contractile dysfunction associated with diabetic cardiomyopathy in hearts from streptozotocin (STZ)-...

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Bibliographic Details
Published in:Cardiovascular research 2008-07, Vol.79 (2), p.322-330
Main Authors: Soliman, Hesham, Craig, Graham P., Nagareddy, Prabhakar, Yuen, Violet G., Lin, Guorong, Kumar, Ujendra, McNeill, John H., MacLeod, Kathleen M.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cardiology. Vascular system
Cells, Cultured
Contractility
Diabetes Mellitus, Experimental - metabolism
Diabetes Mellitus, Experimental - pathology
Diabetes. Impaired glucose tolerance
Diabetic cardiomyopathy
Disease Models, Animal
Dose-Response Relationship, Drug
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Enzyme Inhibitors - pharmacology
Etiopathogenesis. Screening. Investigations. Target tissue resistance
Heart
iNOS
Lipopolysaccharides - pharmacology
Lysine - analogs & derivatives
Lysine - pharmacology
Male
Medical sciences
Myocardial Contraction - drug effects
Myocarditis. Cardiomyopathies
Myocardium - metabolism
Myocardium - pathology
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
Nitric Oxide Donors - pharmacology
Nitric Oxide Synthase Type II - metabolism
Nitroprusside - pharmacology
Rats
Rho kinase
rho-Associated Kinases - metabolism
RhoA
rhoA GTP-Binding Protein - metabolism
Streptozocin
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Summary:Aims Recent studies from our laboratory demonstrated that increased expression of the small GTP-binding protein RhoA and activation of the RhoA/rho kinase (ROCK) pathway play an important role in the contractile dysfunction associated with diabetic cardiomyopathy in hearts from streptozotocin (STZ)-induced diabetic rats. Nitric oxide (NO) has been reported to be a positive regulator of RhoA expression in vascular smooth muscle, and we have previously found that the expression of inducible NO synthase (iNOS) is increased in hearts from STZ-diabetic rats. Therefore, in this study, we investigated the hypothesis that induction of iNOS positively regulates RhoA expression in diabetic rat hearts. Methods and results To determine whether NO and iNOS could increase RhoA expression in the heart, cardiomyocytes from non-diabetic rats were cultured in the presence of the NO donor sodium nitroprusside (SNP) or lipopolysaccharide (LPS) in the absence and presence of the selective iNOS inhibitor, N6-(1-iminoethyl)-l-lysine dihydrochloride (L-NIL). In a second study, 1 week after induction of diabetes with STZ, rats were treated with L-NIL (3 mg/kg/day) for 8 more weeks to determine the effect of iNOS inhibition in vivo on RhoA expression and cardiac contractile function. Expression of iNOS was elevated in cardiomyocytes isolated from diabetic rat hearts. Both SNP and LPS increased RhoA expression in non-diabetic cardiomyocytes. The LPS-induced elevation in RhoA expression was accompanied by an increase in iNOS expression and prevented by L-NIL. Treatment of diabetic rats with L-NIL led to a significant improvement in left ventricular developed pressure and rates of contraction and relaxation concomitant with normalization of total cardiac nitrite levels, RhoA expression, and phosphorylation of the ROCK targets LIM (Lin-11, Isl-1, Mec-3) kinase and ezrin/radixin/moesin. Conclusion These data suggest that iNOS is involved in the increased expression of RhoA in diabetic hearts and that one of the mechanisms by which iNOS inhibition improves cardiac function is by preventing the upregulation of RhoA and its availability for activation.
ISSN:0008-6363
1755-3245
DOI:10.1093/cvr/cvn095