Considerable 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, a promising therapeutic target against various inflammatory and other diseases. Our prior studies provided evidence that the activation of cannabinoid 2 receptors (CB2R) exerts anti-inflammatory effects and attenuates oxidative/nitrative stress in models of liver, cardiovascular and renal injury. However, the detection of the CB2R in cells and tissues is very problematic, because of the lack of specific antibodies. Recently, we have described a novel Photoaffinity Probe That Enables Assessment of CB2R Expression and ligand engagement in human immune cells. Our prior studies also demonstrated that myocardial CB1R contribute to the development of cardiac dysfunction and fibrosis in models of cardiomyopathies and heart failure. Recently, in collaboration with Dr. Thomas Schindler using digital PCR, RNA scope and PET/CT we have found that CB1R is upregulated both in mouse and human hearts in advance obesity. In collaboration with Dr. Kunos we described that CB1R in podocytes contributes both to glomerular and tubular dysfunction and impaired microcirculation in a mouse model of diabetic nephropathy. Our impending 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. Role of oxidative/nitrosative stress, inflammation, metabolic dysregulation in tissue injury Hepatorenal syndrome (HRS) is a very frequent and potentially lethal complication of acute and chronic liver failure (e.g. induced by alcoholic steatohepatitis, cirrhosis, etc.) and is an important predictor of short-term mortality with poor prognosis. The mechanism of acute kidney injury in HRS is poorly understood and there are no clinically relevant animal models for this devastating complication of liver disease. Recently we have described a new clinically relevant mouse model of HRS characterized by tubular injury, tubulointerstitial nephritis and fibrosis that closely resembles the histological features seen in patients suffering from HRS. In this model, disruption of renal arginine metabolism contributed to the impairment of the renal microcirculation and tubular injury, highlighting the importance of interorgan alterations in arginine metabolism in the development of renal injury in HRS. In collaboration with Drs. Zang and Gao we described that DEP domain-containing mTOR-interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute-on-chronic liver injury in alcoholic liver disease. Our collaborative study with Drs. Mehal and Gao found that the widely used heart failure drug digoxin at low doses suppressed pyruvate kinase M2-Promoted HIF-1 transactivation in steatohepatitis models without exerting undesirable cardiac side effects. In a recent collaborative study with Dr. Gao we have shown that alcohol inhibits T-cell glucose metabolism and hepatitis in ALDH2-deficient mice and humans, which involved acetaldehyde and glucocorticoids. Our collaborative study with Dr. Hasko discovered a novel role of Macrophage P2X4 receptors in bacterial killing and sepsis and showed that adenosine receptors differentially regulate type 2 cytokine production by IL-33-activated bone marrow cells, ILC2s, and macrophages Our future collaborative studies with Drs. Kunos, Koob, Gao, and Falk will also explore the role of oxidative/nitrosative stress, inflammation, lipid endocannabinoid signaling and cell death in various new rat and mouse models of alcohol use disorders.
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