Selective Inhibition of Protein Kinase C β2 Attenuates Inducible Nitric Oxide Synthase–Mediated Cardiovascular Abnormalities in Streptozotocin-Induced Diabetic Rats

Abstract

OBJECTIVEImpaired 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-β2 (PKCβ2) dependent and whether selective inhibition of PKCβ reduces iNOS expression and corrects abnormal hemodynamic function in streptozotocin (STZ)-induced diabetic rats.RESEARCH DESIGN AND METHODSCardiomyocytes 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 PKCβ inhibitor, LY333531 (20 nmol/l). Further, the in vivo effects of PKCβ inhibition on iNOS-mediated cardiovascular abnormalities were tested in STZ-induced diabetic rats.RESULTSExposure of cardiomyocytes to high glucose activated PKCβ2 and increased iNOS expression that was prevented by LY333531. Similarly, treatment of VSMC with LY333531 prevented high glucose–induced activation of nuclear factor κB, extracellular signal–related kinase, and iNOS overexpression. Suppression of PKCβ2 expression by small interference RNA decreased high-glucose–induced nuclear factor κB 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.CONCLUSIONSCollectively, these results suggest that inhibition of PKCβ2 may be a useful approach for correcting abnormal hemodynamics in diabetes by preventing iNOS mediated nitrosative stress.

Genistein accelerates refractory wound healing by suppressing superoxide and FoxO1/iNOS pathway in type 1 diabetes

“…Diabetic mice were given intragastrically 1 and 3 mg/kg of L-NIL vehicle (i.e., distilled water) once daily since the date of wounding. The doses of L-NIL were chosen based on previously published data [17,18]. Nondiabetic control received distilled water intragastrically.…”

Time-dependent increases in ouabain-sensitive Na+, K+-ATPase activity in aortas from diabetic rats: The role of prostanoids and protein kinase C

“…Furthermore, alteration of PKC by hyperglycaemia is another pathway associated with micro-and macro-vascular complications observed in diabetic experimental models and patients (Lee et al 1989;Nagareddy et al 2009;Geraldes and King 2010). Among the existing PKC isoforms, the βII PKC is preferentially increased in aorta from diabetic animals (Inoguchi et al 1992;Guo et al 2003) and recent published results suggested that inhibition of PKC-βII may be a useful approach for correcting abnormal cardiovascular alterations present in diabetes (Nagareddy et al 2009;Geraldes and King 2010).…”

“…Moreover, increased cyclooxygenase-derived products such as PGH 2 and TxA 2 are found in experimental diabetes, which contribute to increased vascular contractility (Peredo et al 1999;Xavier et al 2003;Shi and Vanhoutte 2008) and impairment of endothelium-dependent relaxation (Tesfamariam et al 1989;Akamine et al 2006). Furthermore, alteration of PKC by hyperglycaemia is another pathway associated with micro-and macro-vascular complications observed in diabetic experimental models and patients (Lee et al 1989;Nagareddy et al 2009;Geraldes and King 2010). Among the existing PKC isoforms, the βII PKC is preferentially increased in aorta from diabetic animals (Inoguchi et al 1992;Guo et al 2003) and recent published results suggested that inhibition of PKC-βII may be a useful approach for correcting abnormal cardiovascular alterations present in diabetes (Nagareddy et al 2009;Geraldes and King 2010).…”

The Contribution of Endothelial Marker Proteins in the Determination of Vascular Angiogenic Potential, in Normal Physiological Conditions and in Neoplasia

“…In mice and rat models, iNOS was shown to play a significant role in pathological mechanism of several diseases linked to inflammation [44]. This isoform takes part in the development of arterial hypertension, diabetes mellitus or myocardial infarction [12,23,30,44,53,59]. The isoform of eNOS is present in endothelial cells lining the lumen of both the arterial or venous blood vessels, as well as in capillaries and lymphatic vessels.…”

“…TEM7 appears to represent the gene encoding surface proteins of human tumour endothelia which are most frequently expressed [18]. Both the protein and mRNA of TEM7 result in an increased expression of various solid tumours in the endothelia, including carcinomas of the brain, breast, large intestine, lung [30] and in osteogenic sarcomas [14,18]. It provides an opportunity for TEM7-targeted anti-angiogenic therapy, as the physiological ligand of TEM7 and TEM7R, cortactin has been identified.…”