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 endothelial, myocardial and other organ dysfunction in various models of cardiovascular and other injuries, and also in the development of ischemic-reperfusion damage. 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 Doxorubicin(a widely-used chemotherapeutic drug)-induced cell death in cardiomyocytes. Our future studies will explore the role of superoxide, nitric oxide and peroxynitrite and interrelated signaling pathways in heart failure-induced by Doxorubicin.? We have also demonstrated that oxidative inactivation of various key mitochondrial proteins is a pivotal mechanism of organ dysfunction associated with hepatic ischemia/reperfusion injury.? ? 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 aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis. In collaboration with Drs. Szabo and Mabley we have described that the novel inosine analogue, INO-2002, protected against development of diabetes in mice. We have also shown that AdenosineA2A receptor activation inhibits T helper 1 and T helper 2 cell development and effector function. Our impeding studies will also be directed towards the investigation of the role of oxidative/nitrosative stress related pathways in the development of complex hemodynamics alterations associated with diabetic cardiomyopathy, and on the identification of novel therapeutic targets to counteract these pathological processes.? ? In collaboration with Professor David Kass we have created a comprehensive online resource tool for complex hemodynamics measurements in mice using sophisticated pressure-volume (P-V) system for the benefit of cardiovascular research community. We have also used P-V system in various collaborations to characterize complex cardiac function in interesting knockout mice (e.g. in TIP39 knockout mice, collaboration with Dr Ted Usdin). ? ? 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. We have also demonstrated that CB2 cannabinoid receptor activation attenuates TNF-alpha-induced human vascular smooth muscle cell proliferation, migration and interrelated signaling pathways, which may have very important clinical implications for the treatment of atherosclerosis and restenosis. 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, 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. ? 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). ? Our recent collaborative studies with Dr. Rohini Kuner have established an important role for endocannabinoid system in acute and chronic pancreatitis.? 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, which we utilized in our studies and in various collaborations (e.g. with Dr.Ungvari). 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)to address the effects of ethanol on the course of oxidative/nitrosative stress and inflammation associated with aging.
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