Beneficial effect of heme oxygenase-1 expression on myocardial ischemia-reperfusion involves an increase in adiponectin in mildly diabetic rats

Abstract

Transient reduction in coronary perfusion pressure in the isolated mouse heart increases microvascular resistance (paradoxical vasoconstriction) by an endothelium-mediated mechanism. To assess the presence and extent of paradoxical vasoconstriction in hearts from normal and diabetic rats and to determine whether increased heme oxygenase (HO)-1 expression and HO activity, using cobalt protoporphyrin (CoPP), attenuates coronary microvascular response, male Wistar rats were rendered diabetic with nicotinamide/streptozotocin for 2 wk and either CoPP or vehicle was administered by intraperitoneal injection weekly for 3 wk (0.5 mg/100 g body wt). The isolated beating nonworking heart was submitted to transient low perfusion pressure (20 mmHg), and coronary resistance (CR) was measured. During low perfusion pressure, CR increased and was associated with increased lactate release. In diabetic rats, CR was higher, HO-1 expression and endothelial nitric oxide synthase were downregulated, and inducible nitric oxide synthase and O(2)(-) were upregulated. After 3 wk of CoPP treatment, HO activity was significantly increased in the heart. Upregulation of HO-1 expression and HO activity by CoPP resulted in the abolition of paradoxical vasoconstriction and a reduction in oxidative ischemic damage. In addition, there was a marked increase in serum adiponectin. Elevated HO-1 expression was associated with increased expression of cardiac endothelial nitric oxide synthase, B-cell leukemia/lymphoma extra long, and phospho activator protein kinase levels and decreased levels of inducible nitric oxide synthase and malondialdehyde. These results suggest a critical role for HO-1 in microvascular tone control and myocardial protection during ischemia in both normal and mildly diabetic rats through the modulation of constitutive and inducible nitric oxide synthase expression and activity, and an increase in serum adiponectin.

Treatment of Obese Diabetic Mice With a Heme Oxygenase Inducer Reduces Visceral and Subcutaneous Adiposity, Increases Adiponectin Levels, and Improves Insulin Sensitivity and Glucose Tolerance

“…This would confirm the report of Wang et al (47) that showed that the chaperone protein EroL increased adiponectin. We also have previously shown that upregulation of HO-1 protein in diabetic rats provided both cardio-protection and vascular protection against ROS (24).…”

“…Ϫ production (23,24). PPAR␥ agonists are shown to induce both HO-1 (21) and the rate-limiting chaperone protein EroL (46,47).…”

“…Upregulation of HO-1 gene expression prevents vascular dysfunction and endothelial cell death through decreases in ROS levels (23). Recently, L'Abbate et al (24) have shown that induction of HO-1 was associated with a parallel increase in the serum levels of adiponectin, which has well-documented anti-inflammatory properties (24). Adiponectin has been ascribed antioxidative properties (25,26).…”

Cilostazol Inhibits Vascular Smooth Muscle Cell Proliferation and Reactive Oxygen Species Production through Activation of AMP-activated Protein Kinase Induced by Heme Oxygenase-1

“…We first examined whether cilostazol induced HO-1 expression in VSMC, because HO-1 increases the intracellular cAMP levels [20]. HO-1 expression is associated with increases in adiponectin and AMPK activation [21,22]. Our results indicated that cilostazol increased HO-1 and p-AMPK expression with dose-and time-dependent manners (Fig.…”

Role of Heme Oxygenase in Modulating Endothelial Function in Mesenteric Small Resistance Arteries of Spontaneously Hypertensive Rats

“…However, these findings do not necessarily implicate bilirubin as the protective agent given that they are based solely on association studies. Finally, the administration of bilirubin or its precursor biliverdin to rodents can suppress unwanted reactions such as ischemia/reperfusion injury (23,28) and allograft rejection (23,29). However, up until now, few studies have addressed the issue of the role of biliverdin/bilirubin in the prevention of microvascular structural alterations, and in the development of organ damage in hypertension.…”