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). ? In collaboration with Dr. Liaudet we have recently demonstrated that peroxynitrite, a highly reactive oxidant formed from the reaction of nitric oxide and superoxide anion, is a major trigger of cardiomyocyte apoptosis both in vitro and in an in vivo model of myocardial ischemia/reperfusion. Furthermore, we demonstrated modulatory effects of peroxynitrite on various key stress/inflammatory signaling pathways in cardiovascular cell lines. Our future studies will also explore the role of peroxynitrite and/or protein nitration in the apoptosis associated with heart failure and liver ischemia/reperfusion injury using murine models.? ? 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), and PARP inhibitors are beneficial against these pathologies. We also found that aldose reductase inhibition with fidarestat (a promising new drug candidate against diabetic complications) counteracts oxidative-nitrosative stress and poly(ADP-ribose) polymerase activation in tissue sites for diabetes complications. Our impeding studies will also be directed towards the investigation of the effects of PARP inhibitors on VEGF- and FGF-induced angiogenesis which plays pivotal role in the development of various retinopathies and also involved in tumor metastasis formation. ? ? There is accumulating evidence indicating that endocannabinoids and synthetic cannabinergic ligands exert potent antioxidant, cytoprotective and antiinflammatory effects. Our future studies will also examine the effects of various cannabinergic ligands with antioxidant, antiinflammatory, and cytoprotective properties (e.g. cannabidiol) against the development of diabetic 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 also been focused on the involvement of the endocannabinoid system in the hepatic ischemic-reperfusion injury in a mouse model. This is a very appealing area of research because recent accumulating evidence indicates that endocannabinoids and synthetic cannabinergic ligands exert potent anti-inflammatory effects and may also counteract the increased oxidative stress. Our preliminary findings based on pharmacological tools indicate that activation of peripheral CB2 cannabinoid receptors may represent a new protective strategy in various forms of ischemia/reperfusion injury. Our impending studies will also be directed on the understanding of the mechanisms of this protection, especially focusing on the interaction of endothelial, smooth muscle and inflammatory cells.? Our recent collaborative studies with Drs. George Kunos and Raphael Mechoulam have identified N-arachidonoyl L-serine as a new endocannabinoid-like brain constituent with vasodilatory and anti-inflammatory properties. In collaboration with Dr. Kunos we have also characterized the hemodynamic profile of mice lacking fatty acid amide hydrolase (an important enzyme which is also involved in the endocannabinoid degradation) using the sophisticated pressure-volume system.? Our future collaborative studies with Dr. Bin Gao and Dr. George Kunos will also be directed towards the investigation of the role of peripheral CB1, CB2 receptors and endocannabinergic system in various other models of liver injury (e.g. ethanol-induced liver injury) and liver regeneration in mice and rats. ? 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 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. In collaboration with Dr. Ungvari we have recently demonstrated that resveratrol, an atoxic phytoestrogen found in more than 70 plants including grapevine and berries, exerted certain antiinflammatory effects in aging blood vessels.? ? 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 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. Our future collaborative studies with Dr. Bin Gao 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.
Showing the most recent 10 out of 75 publications
