Possible involvement of caveolin in attenuation of cardioprotective effect of ischemic preconditioning in diabetic rat heart

Abstract

BackgroundNitric oxide (NO) has been noted to produce ischemic preconditioning (IPC)-mediated cardioprotection. Caveolin is a negative regulator of NO, which inhibits endothelial nitric oxide synthase (eNOS) by making caveolin-eNOS complex. The expression of caveolin is increased during diabetes mellitus (DM). The present study was designed to investigate the involvement of caveolin in attenuation of the cardioprotective effect of IPC during DM in rat.MethodsExperimental DM was induced by single dose of streptozotocin (50 mg/Kg, i.p,) and animals were used for experiments four weeks later. Isolated heart was mounted on Langendorff's apparatus, and was subjected to 30 min of global ischemia and 120 min of reperfusion. IPC was given by four cycles of 5 min of ischemia and 5 min of reperfusion with Kreb's-Henseleit solution (K-H). Extent of injury was measured in terms of infarct size by triphenyltetrazolium chloride (TTC) staining, and release of lactate dehydrogenase (LDH) and creatin kinase-MB (CK-MB) in coronary effluent. The cardiac release of NO was noted by measuring the level of nitrite in coronary effluent.ResultsIPC- induced cardioprotection and release of NO was significantly decreased in diabetic rat heart. Pre-treatment of diabetic rat with daidzein (DDZ) a caveolin inhibitor (0.2 mg/Kg/s.c), for one week, significantly increased the release of NO and restored the attenuated cardioprotective effect of IPC. Also perfusion of sodium nitrite (10 μM/L), a precursor of NO, significantly restored the lost effect of IPC, similar to daidzein in diabetic rat. Administration of 5-hydroxy deaconate (5-HD), a mito KATP channel blocker, significantly abolished the observed IPC-induced cardioprotection in normal rat or daidzein and sodium nitrite perfused diabetic rat heart alone or in combination.ConclusionsThus, it is suggested that attenuation of the cardioprotection in diabetic heart may be due to decrease the IPC mediated release of NO in the diabetic myocardium, which may be due to up -regulation of caveolin and subsequently decreased activity of eNOS.

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

“…Hotta et al (2010) showed that the angiotensin II subtype 1 receptormediated upregulation of calcineurin in the diabetic rat heart interfered with the phosphorylation of Janusactivated kinase 2 and PI3K-Akt signaling, thereby affecting the efficacy of pharmacologic preconditioning. Ajmani et al (2011) provided data implicating caveolin, which was increased in the diabetic heart and interfered with endothelial NO synthase (eNOS) activity, contributing to the inability of the diabetic heart to respond to ischemic preconditioning. Impaired mitochondrial biogenesis, secondary to a dysfunctional adiponectinadenosine monophosphate-activated kinase (AMPK) axis , and increased TNFa-induced oxidative stress (Su et al, 2013) were also proposed as mechanisms underlying the greater sensitivity of the diabetic heart to ischemia/reperfusion injury and its resistance to ischemic preconditioning.…”

Caveolins; An Assailant or An Ally of Various Cellular Disorders

“…Current document is Daidzein restores the attenuated cardioprotective effect of IPC in ovariectomized rat heart, which may additionally be due to downregulation of caveolin that leads to elevated availability of NO and consequent increase in the activation of mitochondrial K ATP channels. The result show that perfusion of L-NAME, an eNOS inhibitor, and glibenclamide, a K ATP channel blocker, significantly attenuated the DDZ-induced cardioprotective impact of IPC in ovariectomized [83] and diabetic rat heart [13]. Gupta et al mentioned that activation of Heme oxygenase-1 via a specific activator, that is, hemin, restored the attenuated cardioprotective effect of IPC in diabetic rat heart by means of disrupting the caveolin-eNOS complicated and thereby enhancing the release of NO.…”

“…Caveolin is the caveolar membrane protein which invaginated on the plasma layer that fills in as signaling stage for a considerable lot of G-protein coupled receptors [13]. Caveolin-1 gives off an impression of being embedded co-translationally into the ER membrane along its C-and N-terminal segments in the cytoplasm.…”

Sarcolemmal dependence of cardiac protection and stress‐resistance: roles in aged or diseased hearts

“…Potential roles for caveolin‐3 in T1D‐dependent diastolic dysfunction (Lei et al ., ), and impaired GLUT4 translocation (Penumathsa et al ., ) have been revealed in these rat studies. In terms of cardioprotection, one study indirectly implicates a role for elevated caveolin‐1 expression (Ajmani et al ., ), although caveolin levels were not measured and failure of preconditioning not confirmed (with omission of non‐preconditioned diabetic comparators). On the other hand, Li et al .…”