Oxidative-nitrosative stress and poly(ADP-ribose) polymerase in cardiovascular pathophysiology and diabetic complications: cellular and molecular mechanisms.? ? Oxidative/nitrosative stress and consequent PARP activation is a key event in the development of endothelial and myocardial dysfunction in various models of cardiovascular injury and heart failure (ischemic, drug-induced and aging-associated). Importantly, novel drug candidates targeting this pathway entering or being evaluated in Phase II trials for 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 (TAAA), repair surgery and the prevention of complications associated with cardiopulmonary bypass surgery, myocardial infarction (STEMI)undergoing primary percutaneous coronary intervention (PCI).? We have recently demonstrated that peroxynitrite, a highly reactive oxidant formed from the reaction of nitric oxide and superoxide anion, is a key mediator of homocysteine (a recently identified risk factor for various cardiovascular disorders)-induced cell death in cardiomyocytes. Our future studies will also explore the role of superoxide, nitric oxide and peroxynitrite and interrelated signaling pathways in heart failure-induced by widely-used chemotherapeutic drug Doxorubicin. ? Diabetic vascular dysfunction is a major clinical problem which can lead to retinopathy, nephropathy, neuropathy and increased risk of stroke, hypertension and myocardial infarction. In collaboration with Dr. Irina Obrosova we have demonstrated that oxidative-nitrosative stress and poly(ADP-ribose) polymerase (PARP) activation plays a key role in the development of various diabetic complications (including neuropathies, nephropathy and retinopathy). Recently we demonstrated that this pathway is also very important in the development of diabetic sensory neuropathy and neutralization of peroxynitrite or inhibition of PARP can be of significant therapeutics benefit. Our studies have also established that PARP inhibition decreases VEGF- and FGF-induced angiogenesis which plays pivotal role in the development of various retinopathies and also involved in tumor metastasis formation. In collaboration with Dr. George Hasko we have also demonstrated that adenosine receptor activation ameliorates type 1 diabetes in mice, and that A2A receptors are crucially required for IL-10 production by macrophages. Our impeding studies will also be directed towards the role of various oxidative/nitrosative stress related pathways in the development of diabetic cardiomyopathy. ? There is accumulating evidence indicating that endocannabinoids and synthetic cannabinergic ligands exert potent antioxidant, cytoprotective and antiinflammatory effects. Our recent 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 and rat 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 vascular balloon injury-induced neointima formation, oxidative stress and inflammation, and on cardiac and vascular dysfunction associated with advanced aging and doxorubicin-induced heart failure, 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 current 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. ? We have recently found that mice lacking fatty acid amide hydrolase (an important enzyme which is also involved in the endocannabinoid degradation) are more resistant to age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis. Our studies have also showed that the activation of the endocannabinoid system contributes to the cardiotoxicity of the chemotherapeutic agent doxorubicin, and the inhibition of CB1 receptors may afford significant cardioprotection. Our impending studies will also be directed towards the understanding of the mechanisms of this cardioprotective effects, and on the elucidation of the role of endocannabinoid system in various models of cardiomyopathy and heart failure. ? Our recent collaborative studies with Dr. Rohini Kuner have established that in various pain and tissue injury models cannabinoids mediate analgesia largely via peripheral CB1 receptors in nociceptors.? 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. ? ? 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.? ? 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 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.? We have recently developed an assay allowing simultaneous quantitative detection of oxidative stress and aopotosis in virtually any live cells. Our future 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 organ systems. We will use clinically relevant models of aging (Fisher rats developed by National Aging Institute), type 2 diabetes and atherosclerosis to address the effects of ethanol on the course of oxidative/nitrosative stress and inflammation associated with these diseases/pathological states.
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