Overwhelming evidence suggests that oxidative-nitrosative/nitrative stress and inflammation are involved in essentially all major pathological processes affecting humans, including those induced by excessive alcohol consumption. The research focus of the Laboratory of Cardiovascular Physiology and Tissue Injury (LCPTI) to understand the cellular and molecular mechanisms of the complex interplay of oxidative/nitrative stress, inflammation, lipid signaling (for example endocannabinoid signaling) and cell death pathways (e.g. poly(ADP)-ribose polymerase) in tissue injury, and to identify new therapeutic targets using clinically relevant animal models of disease (e.g., ischemia reperfusion injury, cardiomyopathies/heart failure, nephropathies, cardiovascular aging, and alcohol induced cardiovascular, liver and kidney injury and neuroinflammation). Interplay of oxidative/nitrative stress, inflammation with the endocannabinoid system (ES) in tissue injury and inflammation. We have been exploring the interplay of oxidative/nitrative stress, inflammation with the ES; an emerging very promising therapeutic target against various inflammatory and other diseases. Our prior studies provided evidence that the activation of cannabinoid 2 receptors (CB2) exerts anti-inflammatory effects and attenuates oxidative/nitrative stress in models of liver, cardiovascular and renal injury. Recently, in collaboration with Drs. Mario Van der Stelt and Kunos we developed and characterized a novel orally available, peripherally restricted CB2 agonists (LEI-101) with excellent in vivo pharmacological profile and efficacy in an experimental model of nephropathy. In collaboration with Drs. Cinar and Kunos using experimental models of liver fibrosis we also demonstrated antifibrotic effects of a new hybrid inhibitor of peripheral cannabinoid-1 receptor and inducible nitric oxide synthase. Our future studies will also focus on the understanding of the mechanisms of the activation of the endocannabinoid system during tissue injury and on the further elucidation of the role of endocannabinoid system (particularly focusing on the endocannabinoid metabolizing enzymes and CB2 in collaboration with Drs. Cravatt, Van der Stelt, Mechoulam and Kunos) in various models of liver disease, cardiomyopathy and nephropathy. Our future collaborative studies with Drs. George Kunos and Bin Gao will also explore the role of oxidative/nitrosative stress and ES in various other models of liver and metabolic disorders and fibrosis. The above mentioned studies may identify new pharmacological targets in various forms of tissue injury associated with increased inflammation, oxidative stress, and fibrosis. Cannabidiol (CBD) is a nonpsychotropic constituent of marijuana, which is well tolerated in humans, and has been evaluated in numerous clinical trials for various indications. CBD exerts antioxidant and anti-inflammatory effects independent from classic CB1 and CB2. Previously we found that it protected against diabetic and doxorubicin-induced cardiomyopathies by antioxidant and mechanisms and by increasing mitochondrial biogenesis. Recently using a well-established mouse model of experimental autoimmune myocarditis (EAM) induced by immunization with cardiac myosin emmulsified in adjuvant resulting in T cell-mediated inflammation, cardiomyocyte cell death, fibrosis and myocardial dysfunction, we studied the potential beneficial effects of CBD. We found that chronic treatment with CBD largely attenuated the CD3+ and CD4+ mediated inflammatory response and injury, myocardial fibrosis and cardiac dysfunction in mice, suggesting that CBD may represent a promising novel treatment for management of autoimmune myocarditis and possibly other autoimmune disorders, and organ transplantation. Our collaborative studies with Drs. Wu and Gao at FDA demonstrated that trastuzumab (an important drug for the treatment of early stage of breast cancer) via targeting human epidermal growth factor receptor 2 induces hepatotoxicity. Role of oxidative-nitrative stress, inflammation and apoptosis in ethanol-induced tissue-damage. Chronic excessive drinking may promote development of cardiomyopathy and inflammation. Binge drinking is the most common form of alcohol abuse in case of young adults. We recently described novel mouse models of cardiomyopathies induced by chronic plus single or multiple ethanol binges (NIAAA models) and demonstrate that even a single binge can dramatically amplify the deleterious effects of the alcohol in the cardiovascular system. Alcohol binges also induced enhanced myocardial oxidative/nitrative stress (3-NT, gp91phox, p47phox, AGTR1a) and deterioration of mitochondrial complex I, II, IV activities and mitochondrial biogenesis, excessive cardiac steatosis and higher mortality. Our recent ongoing studies are also focused on the understanding of the mechanisms of ethanol-induced oxidative/nitrative stress, inflammation and cell death in the cardiovascular system and also in the liver during various pathological processes (e.g. associated with aging).
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