Heme oxygenase and diabetic heart

Hyperglycemia in diabetes leads to cardiovascular complications induced by oxidative stress. Overall, this independent risk factor worsens cardiac performance, cell survival, and tissue injury following myocardial ischemia/reperfusion (I/R) via increased oxidants and reduced antioxidant defenses. Previous studies showed that the infarct size as a percentage of the left ventricle was significantly greater in STZ hyperglycemic rats as compared with nondiabetic rats, accompanied by impaired levels of the HO-1 within the cardiac tissues associated with increased infarct size. Furthermore the application of I/R caused lower percentage increase of the HO-1 with respect to nondiabetic rats subjected to same procedure. The difference between the levels of HO-1 found in nondiabetic rats and those in STZ rats subjected to I/R argues that ischemic episode–mediated stress, which increases HO-1 in nondiabetic rats, when superimposed on preexisting hyperglycemia-mediated stress, would result in the impairment of the burst of HO-1 expression. This contention is based on preexisting evidence that the concomitant insurgence of both of these situations, hyperglycemia-induced oxidative stress and ischemia-derived stress, limits some transcriptional processes behind HO-1 expression within the myocardial tissue. Diabetic hyperglycemia limits I/R induced expression of the hypoxia inducible factor (HIF)-1 with respect to nondiabetic conditions. HIF-1 is a transcriptional activator of the HO-1 gene in response to cellular hypoxia and stress.

On another note, HO-1 expression may also be impaired by the fact that diabetes and I/R lead to high production of reactive oxygen species and reduced nitric oxide (NO) availability via peroxinitrite formation in the heart. Because normally NO derived from inducible NO synthase (cNOS) enhances HO-1 expression in the tissues, the high peroxinitrite level formed in the heart may have impaired HO-1 expression. Thus, tissue damage parallels the molecular alterations in HO-1. This trend was also copied on cardiovascular parameters. Indeed, there were systemic hemodynamic consequences of HO-1 induction evidenced by monitoring MABP and PRI. HO-1 induction within the heart was associated with a much greater recovery of MABP and PRI toward the physiological values of nondiabetic condition. This is probably due to an increased endogenous CO release that may play a role in the maintenance of vascular and cardiac tone during the reperfusion of ischemic hearts. It is well known that tissues exposed to stress show a correlation between HO-1 and inflammation. The presence of HO-1 in injured tissues represents an adaptive and defensive response to the inflammatory process. Here we show that the impairment of the HO-1 levels induced by hyperglycemia increases the inflammatory component associated with I/R damage. In fact, STZ rats showed higher levels of MPO activity, a marker used to monitor tissue infiltration by PMN, with respect to nondiabetic normoglycemic rats subjected to I/R.

It was found that the casual correlation between cardiac HO-1 expression following I/R and white blood cell recruitment into the myocardium was confirmed on local generation of leukocyte activators, cytokines, and chemokines, which are known to promote leukocyte-endothelium interaction. In addition, hemin-derived HO-1 seems to be capable of inhibiting tissue leukocyte recruitment without affecting their activation, both in nondiabetic and in STZ hyperglycemic rats.