AJP - Heart Calcium Transients and Cell-Sarcomere
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Am J Physiol Heart Circ Physiol 293: H3532-H3541, 2007. First published September 28, 2007; doi:10.1152/ajpheart.00826.2007
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Beneficial effect of heme oxygenase-1 expression on myocardial ischemia-reperfusion involves an increase in adiponectin in mildly diabetic rats

Antonio L'Abbate,1,2 Danilo Neglia,2 Cecilia Vecoli,1 Michela Novelli,3 Virginia Ottaviano,3 Simona Baldi,4 Renata Barsacchi,5 Aldo Paolicchi,3 Pellegrino Masiello,3 George S. Drummond,7 John A. McClung,6 and Nader G. Abraham6,7

1Scuola Superiore Sant'Anna, 2Consiglio Nazionale delle Ricerche Institute of Clinical Physiology, Departments of 3Experimental Pathology, 4Internal Medicine and 5Biology, University of Pisa, Pisa, Italy; and Departments of 6Medicine and 7Pharmacology, New York Medical College, Valhalla, New York

Submitted 16 July 2007 ; accepted in final form 28 September 2007

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 O2– 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.

antiapoptotic signaling protein; superoxide anion; phosphoactivator protein kinase


Address for reprint requests and other correspondence: N. G. Abraham, Dept. of Pharmacology, New York Medical College, Valhalla, NY 10595 (e-mail: nader_abraham{at}nymc.edu) or A. L'Abbate, Scuola Superiore Sant'Anna and CNR Institute of Clinical Physiology, Pisa, 56124 Italy (e-mail: segrlabb{at}ifc.cnr.it)




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