It is proposed that Zn(2+) release during the cardiac cycle results mostly from intracellular free Ca(2+) increase, triggering production of reactive oxygen species that induce changes in metal-binding properties of metallothioneins and other redox-active proteins, aside from ionic exchange on these proteins.

Background and purpose: Reactive oxygen and nitrogen species play an important role in the development of diabetic cardiomyopathy. They can activate matrix metalloproteinases (MMPs), and MMP-2 in particular is known to mediate early consequences of oxidative stress injury in the heart. Therefore, we investigated the role of MMP-2 and the effect of the MMP inhibitor doxycycline on the changes of heart function caused by diabetes. Experimental approach: Using streptozotocin-induced diabetic rats, we evaluated the effect of doxycycline on both mechanical and electrical function of isolated hearts, papillary muscle and cardiomyocytes. Key results: Doxycycline abolished the diabetes-induced depression in left ventricular developed pressure and the rates of changes in developed pressure in isolated hearts and normalized the prolongation of the action potential in papillary muscles. In cardiomyocytes isolated from doxycycline-treated diabetic rats, the altered kinetic parameters of Ca 2 þ transients, depressed Ca 2 þ loading of sarcoplasmic reticulum and basal intracellular Ca 2 þ level, and the spatio-temporal properties of Ca 2 þ sparks were significantly restored. Gelatin zymography and western blot data indicated that the diabetes-induced alterations in MMP-2 activity and protein level, level of tissue inhibitor of matrix metalloproteinase-4 and loss of troponin I were restored to control levels with doxycycline. Conclusions and implications: Our data suggest that these beneficial effects of doxycycline on the mechanical, electrical and biochemical properties of the diabetic rat heart appear, at least in part, to be related to inhibition of MMP activity, implying a role for MMPs in the development of diabetic cardiomyopathy.

Stimulation of local renin-angiotensin system and increased levels of oxidants characterize the diabetic heart. Downregulation of ANG II type 1 receptors (AT1) and enhancement in PKC activity in the heart point out the role of AT1 blockers in diabetes. The purpose of this study was to evaluate a potential role of an AT1 blocker, candesartan, on abnormal Ca 2ϩ release mechanisms and its relationship with PKC in the cardiomyocytes from streptozotocin-induced diabetic rats. Cardiomyocytes were isolated enzymatically and then incubated with either candesartan or a nonspecific PKC inhibitor bisindolylmaleimide I (BIM) for 6 -8 h at 37°C. Both candesartan and BIM applied on diabetic cardiomyocytes significantly restored the altered kinetic parameters of Ca 2ϩ transients, as well as depressed Ca 2ϩ loading of sarcoplasmic reticulum, basal Ca 2ϩ level, and spatiotemporal properties of the Ca 2ϩ sparks. In addition, candesartan and BIM significantly antagonized the hyperphosphorylation of cardiac ryanodine receptor (RyR2) and restored the depleted protein levels of both RyR2 and FK506 binding protein 12.6 (FKBP12.6). Furthermore, candesartan and BIM also reduced the increased PKC levels and oxidized protein thiol level in membrane fraction of diabetic rat cardiomyocytes. Taken together, these data demonstrate that AT 1 receptor blockade protects cardiomyocytes from development of cellular alterations typically associated with Ca 2ϩ release mechanisms in diabetes mellitus. Prevention of these alterations by candesartan may present a useful pharmacological strategy for the treatment of diabetic cardiomyopathy.heart; candesartan; Type 1 diabetes; thiol oxidation CHRONIC DIABETES ALTERS the structure and function of the human heart, and individuals with diabetes mellitus usually develop a specific cardiac dysfunction known as diabetic cardiomyopathy (37). Several mechanisms involved in the development of cardiomyopathy have been postulated, including alterations in intracellular ion homeostasis and glucose metabolism and enhanced oxidative stress. Although alteration of Ca 2ϩ signaling via changes in critical processes that regulate intracellular Ca 2ϩ has become a hallmark of this type of cardiomyopathy, controversies, currently going on, relate to specific alterations in Ca 2ϩ signaling pathways contributing to the cardiac defects in diabetes (7,20). Recently, we reported that these defects result partially from altered local Ca 2ϩ signaling due to a dysfunction of cardiac PKA-mediated ryanodine receptor Ca 2ϩ release channel (RyR2) (51).Several mechanisms have been proposed to explain how all of the pathologies involved in the progression of diabetic cardiomyopathy might result from hyperglycemia. Increased PKC isoform expression and increased polyol pathway flux are two main hypotheses presented to describe how hyperglycemia might cause all of the diabetic complications (6). Furthermore, it has been demonstrated that hyperglycemia activates the local renin-angiotensin system (RAS) and enhanced RAS activity in diabetes (3...

Melatonin has a protective effect on the heart against adriamycin-induced cardiotoxicity in rats.

Increased oxidative stress is one of the basic contributors to the development of the cardiovascular complications in diabetes. Both endothelial and vascular smooth muscle cell dysfunctions are the main sign involved in the pathogenesis of diabetic cardiovascular dysfunction. Matrix metalloproteinases (MMPs) are expressed in the vasculature, and participate in tissue remodeling under pathological conditions such as increased oxidative stress, whereas little is known about effect of hyperglycemia on regulation of MMPs in vascular system. Therefore, we aimed to evaluate the effect of an antioxidant, sodium selenate treatment (0.3 mg/kg for 4 weeks) on function of streptozotocin-diabetic rat aorta. Sodium selenate treatment improved significantly impaired isoproterenol-induced relaxation responses and contraction responses of the aortic strips, and exhibited marked protection against diabetes-induced degenerative changes in the smooth muscle cell morphology. Biochemical data showed that sodium selenate treatment induced a significant regulation of MMP-2 activity and protein loss as well as normalization of increased levels of tissue nitrite and protein thiol oxidation. In addition, this treatment restored diabetes-induced increased levels of endothelin-1, PKC, and cAMP production in the aortic tissue. Taken together, our data demonstrate that these beneficial effects of sodium selenate treatment in diabetics are related to be not only inhibition of increased oxidative stress but also prevention of both receptor- and smooth muscle-mediated dysfunction of vasculature, in part, via regulation of MMP-2. Such an observation provides evidence for potential therapeutic usage of selenium compounds for the amelioration of vascular disorders in diabetes.