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) in tissue injury. Recently 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 previous studies provided evidence that the activation of cannabinoid 1 receptors (CB1) by pathologically dysregulated endocannabinoid system contributed to cardiovascular and renal inflammation and cell death in models of cardiovascular and kidney injury, diabetic retinopathy and diabetic cardiomyopathy. These studies also revealed important interactions of cardiovascular CB1 with angiotensin II receptor type 1 AT1R and its downstream signaling via p47(phox)/ROS-generating NADPH. Our prior in vitro studies have also established that CB1 plays an important role in vascular smooth muscle signaling and proliferation. Our recent collaborative studies with Dr. Sabine Steffens showed that CB1 activation promotes vascular smooth-muscle cell proliferation and neointima formation in an in vivo model of restenosis, raising a possibility that CB1 antagonists would be beneficial in the management or prevention of vascular restenosis complicating coronary angioplasty and vascular surgeries. In collaboration with Dr. Zoltan Benyo we found an important role of CB1 in cerebrocortical blood flow autoregulation. In earlier studies using models of hepatic ischemia/reperfusion injury we demonstrated that oxidative/nitrosative/nitrative stress is involved in the marked activation of the ES during reperfusion injury. In a recent study we explored the role of endocannabinoids and their metabolism during acute liver injury. We revealed very interesting interactions of endocannabinoid and eicosanoid lipid signaling pathways in controlling acute liver injury induced by various triggers. We demonstrated a key role for monoacylglycerol lipase (MAGL), one of the main endocannabinoid degrading enzymes, linking these pathways, hydrolyzing the endocannabinoid 2-arachidonoylglycerol to generate the arachidonic acid precursor pool for prostaglandin production. We showed that MAGL inhibition decreases hepatic injury via dual control over endocannabinoid-CB2 receptor and eicosanoid signaling pathways, suggesting that MAGL inhibitors might be developed to treat conditions that expose the liver to acute oxidative stress and inflammatory damage. Our upcoming 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, Nomura 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 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. Our collaborative studies with Dr. Gyorgy Hasko revealed that adenosine augmented IL-10-induced STAT3 signaling in M2c macrophages and that stimulation of A2B adenosine receptors protected against trauma-hemorrhagic shock-induced lung injury. In collaboration with Dr. Esther Sternberg we have demonstrated that glucocorticoid receptor dimerization was required for proper recovery from endotoxin-induced inflammation, sickness behavior and metabolism in mice. With Dr. Lucas Liaudet we recently demonstrated that the potent oxidant and nitrating species peroxynitrite may be responsible for the protection observed during ischemic post-conditioning in the heart, suggesting that reactive oxidants may modulate very specific signaling processes to exert context-dependent effects, including activation of various endogenous protective mechanisms. Role of oxidative-nitrative stress, inflammation 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. 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 pathological processes (e.g. associated with aging). Through collaboration with Drs. Emanuel Rubin and Gyorgy Hajnoczky at Dept. of Pathology, Thomas Jefferson University, we will also assess tissue samples from alcoholics to investigate the role of oxidative stress and inflammatory signaling in alcohol-induced myocardial and skeletal muscle injury.

Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2013
Total Cost
$1,207,542
Indirect Cost
Name
National Institute on Alcohol Abuse and Alcoholism
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Type
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Liaudet, Lucas; Calderari, Belinda; Pacher, Pal (2014) Pathophysiological mechanisms of catecholamine and cocaine-mediated cardiotoxicity. Heart Fail Rev :
Csoka, Balazs; Koscso, Balazs; Toro, Gabor et al. (2014) A2B adenosine receptors prevent insulin resistance by inhibiting adipose tissue inflammation via maintaining alternative macrophage activation. Diabetes 63:850-66
Mukhopadhyay, Partha; Rajesh, Mohanraj; Cao, Zongxian et al. (2014) Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis. Hepatology 59:1998-2009
Erdelyi, Katalin; Pacher, Pal; Virag, Laszlo et al. (2013) Role of poly(ADP-ribosyl)ation in a 'two-hit' model of hypoxia and oxidative stress in human A549 epithelial cells in vitro. Int J Mol Med 32:339-46
Pacher, Pal; Kunos, George (2013) Modulating the endocannabinoid system in human health and disease--successes and failures. FEBS J 280:1918-43
Koscso, Balazs; Trepakov, Alexey; Csoka, Balazs et al. (2013) Stimulation of A2B adenosine receptors protects against trauma-hemorrhagic shock-induced lung injury. Purinergic Signal 9:427-32
Silverman, M N; Mukhopadhyay, P; Belyavskaya, E et al. (2013) Glucocorticoid receptor dimerization is required for proper recovery of LPS-induced inflammation, sickness behavior and metabolism in mice. Mol Psychiatry 18:1006-17
Li, Jianhui; Loukili, Noureddine; Rosenblatt-Velin, Nathalie et al. (2013) Peroxynitrite is a key mediator of the cardioprotection afforded by ischemic postconditioning in vivo. PLoS One 8:e70331
Molica, Filippo; Burger, Fabienne; Thomas, Aurelien et al. (2013) Endogenous cannabinoid receptor CB1 activation promotes vascular smooth-muscle cell proliferation and neointima formation. J Lipid Res 54:1360-8
Liaudet, Lucas; Rosenblatt-Velin, Nathalie; Pacher, Pal (2013) Role of peroxynitrite in the cardiovascular dysfunction of septic shock. Curr Vasc Pharmacol 11:196-207

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