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Published on: May 12, 2019
Methamphetamine causes cardiovascular dysfunction via cystathionine gamma lyase and hydrogen sulfide depletion
Gopi K Kolluru1, John D Glawe1, Sibile Pardue1
1Department of Pathology, LSU Health Sciences Center- Shreveport, USA.
Insights
Methamphetamine use damages blood vessels and heart function by disrupting the cystathionine gamma lyase (CSE)/hydrogen sulfide (H2S)/nitric oxide (NO) pathway. Restoring H2S levels may protect against methamphetamine-induced cardiovascular disease.
Area of Science:
- Cardiovascular Biology
- Pharmacology
- Biochemistry
Background:
- Methamphetamine (METH) use is a global issue linked to escalating cardiovascular disease (CVD) in younger individuals.
- METH abuse is associated with hypertension, vasospasm, left ventricular hypertrophy, and coronary artery disease.
Purpose of the Study:
- To investigate the role of the cystathionine gamma lyase (CSE)/hydrogen sulfide (H2S)/nitric oxide (NO) pathway in METH-induced cardiovascular dysfunction.
- To explore therapeutic strategies targeting this pathway for METH-related CVD.
Main Methods:
- METH administration in a mouse 'binge and crash' model.
- Assessment of cardiovascular function, endothelial function (flow-mediated vasodilation, blood flow velocity), and cardiac performance (ejection fraction, fractional shortening).
- Measurement of H2S and NO bioavailability, CSE expression, and eNOS phosphorylation in plasma and tissues.
Main Results:
- METH significantly impaired cardiovascular function, reduced H2S and NO bioavailability, and decreased flow-mediated vasodilation and blood flow velocity, indicating endothelial dysfunction.
- METH induced cardiac dysfunction, characterized by reduced ejection fraction and fractional shortening, alongside increased fibrosis.
- METH selectively downregulated CSE expression and sulfide levels, and reduced eNOS phosphorylation and NO production.
- Exogenous sulfide therapy or endothelial CSE overexpression ameliorated METH-induced cardiovascular and pathological changes.
Conclusions:
- METH impairs cardiovascular function through a pathway involving decreased CSE/H2S/NO signaling.
- Therapeutic interventions targeting the CSE/H2S pathway show promise in mitigating METH-associated cardiovascular damage.
Abstract:
Methamphetamine (METH) is an addictive illicit drug used worldwide that causes significant damage to blood vessels resulting in cardiovascular dysfunction. Recent studies highlight increased prevalence of cardiovascular disease (CVD) and associated complications including hypertension, vasospasm, left ventricular hypertrophy, and coronary artery disease in younger populations due to METH use. Here we report that METH administration in a mouse model of 'binge and crash' decreases cardiovascular function via cystathionine gamma lyase (CSE), hydrogen sulfide (H2S), nitric oxide (NO) (CSE/H2S/NO) dependent pathway. METH significantly reduced H2S and NO bioavailability in plasma and skeletal muscle tissues co-incident with a significant reduction in flow-mediated vasodilation (FMD) and blood flow velocity revealing endothelial dysfunction. METH administration also reduced cardiac ejection fraction (EF) and fractional shortening (FS) associated with increased tissue and perivascular fibrosis. Importantly, METH treatment selectively decreased CSE expression and sulfide bioavailability along with reduced eNOS phosphorylation and NO levels. Exogenous sulfide therapy or endothelial CSE transgenic overexpression corrected cardiovascular and associated pathological responses due to METH implicating a central molecular regulatory pathway for tissue pathology. These findings reveal that therapeutic intervention targeting CSE/H2S bioavailability may be useful in attenuating METH mediated cardiovascular disease.
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