Mechanism of oxidative/nitrosative stress and inflammation-induced tissue injury

National Institute On Alcohol Abuse And Alcoholism

Investigators

Linked publications, trials & patents

Abstract

Interplay of oxidative/nitrative stress, inflammation with the endocannabinoid system (ES) in tissue injury and inflammation. Binge drinking is linked to acute cardiovascular complications, including depressed cardiac performance, arrhythmias, and blood-pressure instability. We recently showed that even a single alcohol binge in mice produces complex, profound cardiovascular effects with transient but marked depression of myocardial contractility. These effects are mediated, at least in part, by activation of the endocannabinoid–CB1 receptor (CB1R) axis, which is also implicated in the progression of heart failure, arrhythmias, and atherosclerosis. Consistent with this mechanism, numerous recent case reports and clinical studies indicate that cannabinoids—such as Δ9-tetrahydrocannabinol (THC) and more potent synthetic analogs (“spice”)—can adversely affect the cardiovascular system via CB1R activation, precipitating myocardial infarction, cardiomyopathy, tachyarrhythmias, stroke, or cardiac arrest. Alarming trends in polydrug misuse, particularly among young adults, have been associated with increasing morbidity and mortality, although the underlying mechanisms remain incompletely defined. In our recent study employing pressure–volume (PV) loop analysis, we characterized the cardiac impact of combined acute alcohol and synthetic cannabinoid exposure. Simultaneous administration produced profound cardiac dysfunction. Intravenous rimonabant (a CB1R antagonist) largely reversed these effects, whereas intracerebroventricular administration yielded only partial recovery—implicating both peripheral and central CB1R signaling in the observed cardiodepression. These data support repurposing CB1R antagonists as emergency countermeasures to mitigate life-threatening cardiodepression during acute alcohol–cannabinoid co-exposure. The cannabinoid receptor 2 (CB2R), predominant on myeloid/lymphoid cells and inducible in inflamed tissues—is a non-psychoactive anti-inflammatory target. Translation is limited by poor antibody specificity, non-selective ligands, and unclear, context-dependent signaling. In collaboration with various academic institutions and industry partners, our ongoing research focuses on developing and characterizing improved CB2R ligands, while investigating the role of CB2Rs in inflammation within the brain, kidneys, and liver. Additionally, our collaborative work with Dr. Yuri Persidsky explores the involvement of CB2R in AIDS pathology using humanized mouse models. Role of oxidative/nitrosative stress, inflammation, metabolic dysregulation in tissue injury Aging drives functional decline across tissues and heightens risk for cardiometabolic disease, yet its tissue-specific molecular drivers remain incompletely defined. Leveraging data from the Genotype-Tissue Expression (GTEx) project, we analyzed transcriptomes from 40 human tissues, comparing individuals <40 to >65 years. We identified >17,000 differentially expressed genes with consistent pathway shifts: inflammation/immune and apoptosis programs were upregulated, whereas mitochondrial function, oxidative phosphorylation, and metabolic processes were downregulated. Gene co-expression network analysis highlighted 1,099 cross-tissue dysregulated nodes, indicating a shared aging architecture. Integrating machine learning, we prioritized biomarkers—most notably GDF15 and EDA2R—that robustly predict age and are enriched in cardiometabolic tissues (heart, liver, skeletal muscle, adipose). These signals were validated in plasma proteomics and correlated with clinical cardiometabolic indicators. This multi-tissue atlas delineates systemic and organ-specific aging signatures and nominates actionable biomarkers and pathways to guide risk stratification and therapeutic targeting for healthy aging. Building on our rodent and human studies identifying PCSK9 as a potential therapeutic target and biomarker for cardiometabolic aging, in collaboration with Dr. Lohoff’s group we evaluated type 2 diabetes (T2D) risk of PCSK9 and HMGCR (statin-pathway) inhibitors, which are widely used to decrease LDL cholesterol levels and cardiovascular morbidity/mortality, in a multi-ancestry Mendelian randomization study across five populations. Genetically proxied long-term PCSK9 inhibition showed largely neutral associations with T2D and glycemic traits in most groups, whereas HMGCR inhibition was linked to higher T2D risk in several populations. These findings suggest PCSK9 inhibition may have a more favorable metabolic profile than HMGCR inhibition and underscore the value of ancestry-aware, genetics-guided therapy selection and risk stratification. The pathology of cardiovascular aging is complex, involving mitochondrial dysfunction, oxidative and nitrative stress, oxidative DNA injury, impaired lipid metabolism, cell death, senescence, and chronic inflammation. These processes lead to remodeling and structural changes in the cardiovascular system, resulting in a progressive decline in cardiovascular reserve capacity and health, and an increased risk of diseases and mortality. Excessive alcohol consumption exacerbates these risks by promoting hypertension, atrial and ventricular arrhythmias, ischemic heart disease, cardiomyopathy, stroke, and sudden cardiac death in the general population. Among people over 65 years old, cardiovascular disease is the primary health burden associated with alcohol consumption. Yet mechanistic and longitudinal data specific to older adults—who already face high baseline cardiovascular risk—remain limited, even as alcohol use is rising in this age group. To address this gap, we investigated the effects of a 6-month 5% Lieber–DeCarli alcohol diet in young (3-month) and aged (24–26-month) Fischer F344×BN F1 rats—an established, clinically relevant model of cardiovascular aging. Chronic alcohol consumption in both young and aging rats decreased mitochondrial function, disrupted cholesterol and triglyceride metabolism, and increased oxidative/nitrative stress, inflammation, cell death, and senescence, leading to a decline in systolic contractile function. In aging rats, alcohol further exacerbated diastolic dysfunction and myocardial fibrosis. Alcohol also increased oxidative/nitrative stress, apoptosis, and senescence in the vasculature, contributing to endothelial dysfunction and increased total peripheral resistance. Additionally, alcohol exacerbated aging-related ventriculo-arterial uncoupling (a risk factor for cardiovascular mortality), and diminished cardiac efficiency, further reducing cardiovascular reserve capacity. This study highlights alcohol’s role as an accelerant of cardiovascular aging, emphasizing the need for health care professionals and public health experts to recognize alcohol as a modifiable risk factor in cardiovascular aging. Peripheral artery disease (PAD) is an age-associated vascular disorder that drives progressive, ischemia-related skeletal muscle dysfunction characterized by oxidative stress, mitochondrial abnormalities, and atrophy. Although alcohol use and high-fat diets are linked to increased PAD risk and severity, their direct effects on PAD myopathy remain poorly defined. In a recent proof-of-concept study with Dr. Koutakis, we showed that prolonged ethanol exposure combined with a high-fat, high-fructose diet markedly exacerbates skeletal muscle degeneration in aged mice with chronic hindlimb ischemia, accompanied by mitochondrial dysfunction and dysregulation of ALDH2. In future studies, we will evaluate alcohol’s effects on skeletal-muscle pathology in patients with PAD and identify potential therapeutic targets to restore mitochondrial function and enhance aldehyde detoxification. CD39 or NTPDase1 and other nucleoside triphosphate diphosphohydrolases (NTPDases), including NTPDase2, NTPDase3, and NTPDase8, regulate purinergic signaling through tuning the extracellular levels of purine nucleotides and nucleosides. In a recent collaborative preclinical study with Dr. Hasko we discovered differential roles of NTPDase family members in liver injury, with parenchymal/hepatocyte expression of NTPDase8 emerging as a critical suppressor of the inflammatory and metabolic responses to hepatic injury, even in the presence of vascular NTPDase1 expression. Chemotherapy-induced cognitive impairment, commonly referred to as "chemobrain," is a frequent and debilitating side effect experienced by cancer survivors treated with paclitaxel (PTX). Our recent collaborative study with Dr. Ungvari suggests that targeting endothelial senescence and its downstream effects could mitigate PTX-induced blood-brain barrier dysfunction and associated cognitive impairments.