Oxidative-nitrosative stress and poly(ADP-ribose) polymerase in cardiovascular pathophysiology, ischemia/reperfusion injury and diabetic complications: cellular and molecular mechanisms. Oxidative/nitrosative stress-PARP pathway is a key event in the development of cardiovascular and other organ dysfunction in various diseases, and also in the development of ischemic-reperfusion damage. Novel drug candidates targeting this pathway entering or being evaluated in trials for cancer and a variety of critical care diseases associated with reperfusion injury and inflammation, including but not limited to ischemic stroke, acute respiratory distress syndrome, thoraco-abdominal aortic aneurism, repair surgery and the prevention of complications associated with cardiopulmonary bypass surgery, myocardial infarction undergoing primary percutaneous coronary intervention. We have recently demonstrated that mitochondrial reactive oxygen and nitrogen species generation is the major trigger of tissue injury and myocardial dysfunction in a well-established doxorubicin-induced heart failure model. Consequently, scavenging these reactive oxidants attenuated the oxidative/nitrosative stress, cell death and the activation of various interrelated signaling pathways (e.g. PARP) and cardiac dysfunction. In collaboration with Dr. Jon Mabley we have identified a novel role for PARP in polychlorinated biphenyls (environmental pollutants)-induced endothelial cell dysfunction. Cardiovascular complications are the most common cause of morbidity and mortality in diabetic patients. The presence of myocardial dysfunction independent of coronary artery disease in diabetes, known as """"""""diabetic cardiomyopathy,"""""""" has been well documented in both humans and animals. We have recently characterized the major sources/role of oxidative/nitrosative stress in the development of myocardial dysfunction in a well-established type I diabetic cardiomyopathy model. We have demonstrated that the enzyme xanthine oxidase (XO), which is also frequently overexpressed in patients with heart failure, is an important source of oxidative stress in diabetic cardiomyopathy. We found that inhibition of this enzyme with a clinically used XO inhibitor, allopurinol, attenuated the oxidative/nitrosative stress, fibrosis, activation of interrelated signaling pathways and cardiac dysfunction. Our impeding studies will be directed towards the identification of novel therapeutic targets to counteract these pathological processes. There is accumulating evidence indicating that endocannabinoids and synthetic cannabinergic ligands exert potent antioxidant, cytoprotective and immunomodulatory effects. Our previous studies showed that the non-psychoactive cannabinoid cannabidiol attenuated the high glucose-induced endothelial cell activation and barrier disruption, which are crucial early event underlying the development of various diabetic complications and atherosclerosis. Our future studies will also examine the role of endocannabinoid system in the development of diabetic cardiovascular complications using mouse models of type 1 diabetes. These studies will also be extended to investigate the antioxidant/anti-inflammatory effects of various cannabinergic ligands on the development of oxidative stress and inflammation, and on cardiac and vascular dysfunction associated with advanced aging and doxorubicin-induced heart failure, and ischemia-reperfusion, conditions also known to be associated with increased oxidative/nitrosative stress and PARP activation, in relevant animal models. Role of endocannabinoid system in tissue injury and inflammation. Our previous studies have been focused on the role of the endocannabinoid system (ES) in the hepatic ischemic-reperfusion injury in a mouse model. These studies have demonstrated that oxidative/nitrosative stress is involved in the activation of the ES, and the stimulation of peripheral CB2 cannabinoid receptors protected against I/R-induced tissue injury by decreasing endothelial cell activation and inflammatory response and interrelated oxidative/nitrosative stress. In a recent collaborative study with Dr. Gyorgy Hasko we found that the above mentioned immunosuppressive effects of CB2 activation by endocannabinoids (which is beneficial in sterile models of inflammation), may lead to enhanced bacterial invasion and consequent increased inflammation and tissue injury in a model of bacterial sepsis with live bacteria. In collaboration with Dr. Bin Gao we have recently demonstrated that cannabidiol, a nonpsychoactive constituent of Cannabis Sativa, which has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in patients, attenuated the important chemotherapeutic drug cisplatin-induced nephrotoxicity by decreasing oxidative/nitrosative stress, inflammation, and interrelated cell death pathways. Our impending studies will also be directed towards the understanding of the mechanisms of the activation of the endocannabinoid system during reperfusion injury and on the elucidation of the role of endocannabinoid system in various models of cardiomyopathy and heart failure (e.g. doxorubicin-induced heart failure and diabetic cardiomyopathy). The above mentioned studies may identify new pharmacological targets in various forms of tissue injury and cardiovascular dysfunction associated with increased inflammation and oxidative stress. Our future collaborative studies with Drs. George Kunos, Bin Gao and Byoung-Joon Song will also be directed towards the investigation of the role of oxidative/nitrosative stress and endocannabinoid system in various other models of liver and metabolic disorders. Role of oxidative-nitrosative stress and apoptosis in ethanol-induced tissue-damage. Moderate and heavy drinking may significantly influence cardiovascular function and aging in different ways. During the course of the last decade, several research groups have reported that, in animal models of myocardial ischemia/reperfusion ethanol and non-ethanolic components of wine may have a specific protective effect on the myocardium, independent of the classical risk factors implicated in vascular atherosclerosis and thrombosis. Apoptosis is a mechanism of cell death implicated in the pathogenesis of alcohol-induced organ damage. Experimental studies have suggested alcohol-mediated apoptosis in the cardiac muscle and liver, and there is also evidence of skeletal muscle apoptosis in long-term high-dose alcohol consumers. Apoptosis is present to a similar degree in the heart muscle of high-dose alcohol consumers and long-standing hypertensive subjects and is related to structural damage. In several recent collaborative studies with Dr. Zoltan Ungvari we have evaluated the mechanism of the beneficial effects of resveratrol, a polyphenolic constituent of red wine, in cells of the cardiovascular system. We have found that resveratrol induced mitochondrial biogenesis in endothelial cells and markedly attenuated the mitochondrial ROS production. In collaboration with Madesh Muniswamy, we have identified a new mitochondrial superoxide-dependent pathway, which may be involved in the hepatotoxicity of ethanol. Our impending studies will be focused on the understanding of the mechanisms of ethanol-induced oxidative/nitrosative stress and apoptosis in the cardiovascular system and also in other organs. We will use clinically relevant models of aging (Fisher rats developed by National Aging Institute) to address the effects of ethanol on the course of oxidative/nitrosative stress and inflammation associated with aging.
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