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 SOSTI is to understand the cellular and molecular mechanisms underlying oxidative/nitrosative/nitrative stress, inflammation, and their downstream effector pathways using clinically relevant animal models of disease (e.g. ischemia reperfusion injury, cardiomyopathy/heart failure), and to identify novel therapeutic targets against these pathologies. Interplay of oxidative/nitrative stress, inflammation with the endocannabinoid system (ES), and natural plant derived cannabinoids in tissue injury. During the last couple of years we have explored the interplay of oxidative/nitrative stress, inflammation with the ES;an emerging very promising therapeutic target against various inflammatory and other diseases. Our previous in vitro studies suggested that cannabinoid 1 receptor (CB1) activation by endocannabinoid anandamide (AEA) in human coronary endothelial cells and cardiomyocytes may amplify the reactive oxygen species (ROS)-MAPK activation-cell death pathway in pathological conditions when the endocannabinoid biosynthetic or metabolic pathways are dysregulated by excessive inflammation and/or oxidative/nitrosative stress, thereby contributing to the development of endothelial dysfunction and pathophysiology of multiple cardiovascular diseases. We provided evidence that CB1 activation contributed to vascular inflammation and cell death in a mouse model of diabetic retinopathy and in a primary retinal cells. Recently we also discovered novel interactions of cardiovascular CB1 with angiotensin II receptor type 1 AT1R and its downstream signaling via p47(phox)/ROS-generating NADPH enzyme isoform, advanced glycation end product (AGE)-receptor (RAGE), and other pro-inflammatory/pro-oxidant signaling pathways in diabetic cardiovascular tissues, which may underlie the development of multiple diabetic complications. We found that diabetic cardiomyopathy was characterized by increased myocardial endocannabinoid anandamide levels, oxidative/nitrative stress, activation of p38/Jun MAPKs, enhanced inflammation, increased expression of CB1, RAGE, AT1R, p47(phox) NADPH oxidase subunit, β-myosin heavy chain isozyme switch, accumulation of AGE, fibrosis, and decreased expression of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase. Pharmacological inhibition or genetic deletion of CB1 receptors attenuated the diabetes-induced cardiac dysfunction and the above-mentioned pathological alterations. Our previous studies using acute models of hepatic ischemia/reperfusion injury also demonstrated that oxidative/nitrosative/nitrative stress is involved in the marked activation of the ES during reperfusion injury. Our impending studies will be directed towards the understanding of the precise triggers and mechanisms of the activation of the endocannabinoid system during tissue injury. In collaboration with Drs. Kalyanaraman, Zsengeller and Stillman we have recently studies the potential role of mitochondrial ROS generation in the pro-inflammatory response associated with hepatic ischemia/reperfusion injury and nephropathy induced by a widely used chemotherapeutic drug cisplatin. These studies demonstrated that mitochondrially generated oxidants play a central role in triggering the deleterious cascade of events associated with liver and kidney injury, which could be targeted by novel antioxidants for therapeutic advantage. Our previous and current studies have also identified a key role for peripheral cannabinoid 2 receptors (CB2) in regulating inflammation and tissue injury, and in collaboration with Professor Mechoulam and Pertwee we have developed novel CB2 receptor agonists, and explored the therapeutic potential of various natural cannabinoids and their derivatives for various therapeutic indications associated with oxidative stress and inflammation, such as associated with ischemia reperfusion injury. In collaboration with Dr. Sabine Steffens we have recently discovered that CB2 receptors play an important role in limiting the pathological vascular smooth muscle proliferation and macrophage infiltration during vascular injury. These results suggest that CB2 receptor agonists may be beneficial in attenuating pathological vascular remodeling following coronary bypass surgery. Our recent studies also suggest that certain purified plant (not marijuana) derived oils which are widely used in alternative medicine, contain powerful anti-inflammatory compounds which are potent natural CB2 agonists. In collaboration with Dr. Gertsch we recently found that β-caryophyllene (BCP), a natural sesquiterpene found in many essential oils of spice, dose-dependently ameliorated cisplatin-induced kidney dysfunction, morphological damage, and renal inflammatory response induced by cisplatin. It also markedly mitigated oxidative/nitrative stress and cell death. The protective effects of BCP against biochemical and histological markers of nephropathy were absent in CB2 knockout mice. Thus, BCP may be an excellent therapeutic agent to prevent cisplatin-induced nephrotoxicity through a CB2 receptor-dependent pathway. Given the excellent safety profile of BCP in humans it has tremendous therapeutic potential in a multitude of diseases associated with inflammation and oxidative stress. Our future studies will also be directed towards the understanding of the mechanisms of the activation of the endocannabinoid system during reperfusion injury and on the further elucidation of the role of endocannabinoid system (particularly focusing on the endocannabinoid metabolizing enzymes in collaboration with Drs. Cravatt and Kunos) in various models of cardiomyopathy and nephropathy. Our future collaborative studies with Drs. George Kunos, Bin Gao and Byoung-Joon Song will also explore the role of oxidative/nitrosative stress and ES in various other models of liver and metabolic disorders. The above mentioned studies may identify new pharmacological targets in various forms of tissue injury associated with increased inflammation and oxidative stress. Role of oxidative-nitrative stress and apoptosis in ethanol-induced tissue-damage. Moderate and heavy drinking may significantly influence cardiovascular function in different ways. During the course of the last decade, several research groups have reported that, in models of myocardial ischemia/reperfusion injury using young rodents, low dose ethanol or non-ethanolic components of wine (e.g. resveratrol) may exert acute cardioprotective effect independent of the classical risk factors implicated in vascular atherosclerosis and thrombosis. However, chronic drinking may also lead to the development of cardiomyopathy and potent immunomodulatory effects. Alcohol-mediated apoptosis of cardiomyocytes has been documented in experimental animals, and there is also evidence of skeletal muscle cell apoptosis in chronic heavy drinkers. The extent of apoptotic damage in the heart is similar in heavy drinkers and in patients with long-standing hypertension and is related to structural damage. Through collaboration with Drs. Emanuel Rubin and Gyorgy Hajnoczky at Dept. of Pathology, Thomas Jefferson University, we will be able to access unique tissue samples from alcoholics to investigate the role of oxidative stress and inflammatory signaling in alcohol-induced myocardial and skeletal muscle injury. Our future studies will be 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 pathological processes (e.g. associated with aging).

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National Institute on Alcohol Abuse and Alcoholism
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