Effects of Cocaine on Intracellular Calcium Handling In Cardiac and Vascular Smooth Muscle

Perreault, C. L.; Morgan, K. G.

doi:10.1037/e496272006-013

Cited by 5 publications

(5 citation statements)

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“…As such, cocaine induces sympathetic effects on the cardiovascular system by enhanced inotropic and chronotropic effects through increased vasoconstriction. In particular, cocaine induces acute hypertension due to increased vasoconstriction induced by increased endothelin-1 [16], impaired acetylcholine-induced vasorelaxation [17], inhibition of nitric oxide synthase [18], impaired intracellular calcium handling [19], and inhibition of sodium/potassium channels [20] as determined by cellular and molecular analytical approaches [11]. In addition, acute vessel damage induces platelet aggregation/blood clots through increased fibrinogen and von Willebrand factor, leading to acute heart damage due to reduced blood flow [21].…”

Section: Pathophysiological Mechanisms Of Cocaine On Cardiovasculamentioning

confidence: 99%

Acute and Chronic Effects of Cocaine on Cardiovascular Health

Kim

Park

2019

IJMS

104

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Cardiac complications resulting from cocaine use have been extensively studied because of the complicated pathophysiological mechanisms. This study aims to review the underlying cellular and molecular mechanisms of acute and chronic effects of cocaine on the cardiovascular system with a specific focus on human studies. Studies have consistently reported the acute effects of cocaine on the heart (e.g., electrocardiographic abnormalities, acute hypertension, arrhythmia, and acute myocardial infarction) through multifactorial mechanisms. However, variable results have been reported for the chronic effects of cocaine. Some studies found no association of cocaine use with coronary artery disease (CAD), while others reported its association with subclinical coronary atherosclerosis. These inconsistent findings might be due to the heterogeneity of study subjects with regard to cardiac risk. After cocaine use, populations at high risk for CAD experienced coronary atherosclerosis whereas those at low risk did not experience CAD, suggesting that the chronic effects of cocaine were more likely to be prominent among individuals with higher CAD risk. Studies also suggested that risky behaviors and cardiovascular risks may affect the association between cocaine use and mortality. Our study findings highlight the need for education regarding the deleterious effects of cocaine, and access to interventions for cocaine abusers.

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Section: Pathophysiological Mechanisms Of Cocaine On Cardiovasculamentioning

confidence: 99%

Acute and Chronic Effects of Cocaine on Cardiovascular Health

Kim

Park

2019

IJMS

104

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“…These sympathomimetic effects led to the stimulation of cardiomyocyte adrenergic receptors resulting in increased heart rate, BP, and vasoconstriction that, in turn, increases myocardial oxygen demand. The sympathomimetic effects can cause elevated levels of the vasoconstrictor protein endothelin-1 56 , increased ROS levels 30 , inhibition of nitric oxide (NO) synthase 19 , impaired acetylcholine-induced vasorelaxation 57 , and the dysregulation of intracellular calcium levels 58 . Although the sympathomimetic mechanisms contribute to CV disorders, they can’t explain the full extent and the diversity of cocaine-induced CV phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…By modulating Cacna2d2 expression, miR-423-5p was found to control [Ca 2+ ] i and, in turn, SMC contractility. It is well established that the regulation of [Ca 2+ ] i levels plays a critical role in regulating SMC contractility and the development of myocardial ischemia, infarction, HTN, and arrhythmia 18,49,58,66 . L-type Ca v 1.2 channels (LTCCs) are the principal channels involved in mediating the influx of Ca 2+ and the regulation of myogenic tone 49-51 Overexpression of miR-423-5p resulted in reduced SMC contractility in the presence of cocaine.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-423-5p Mediates Cocaine-Induced Smooth Muscle Cell Contraction by Targeting Cacna2d2

Dykxhoorn

Wang

Ferreira³

et al. 2023

Preprint

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Background: Cocaine abuse increases the risk of atherosclerotic cardiovascular disease (CVD) and causes acute coronary syndromes (ACS) and hypertension (HTN). Significant research has explored the role of the sympathetic nervous system mediating the cocaine effects on the cardiovascular (CV) system. However, the response of the sympathetic nervous system alone is insufficient to completely account for the CV consequences seen in cocaine users. Here, we examined the role of microRNAs (miRNAs) in mediating the effect of cocaine on the CV system. MiRNAs regulate many important biological processes and have been associated with both response to cocaine and CV disease development. Multiple miRNAs have altered expression in the CV system (CVS) upon cocaine exposure. Herein, we examined the role of microRNA-423-5p and the downstream signaling events in regulating cocaine-induced mouse aortic smooth muscle cell (SMC) contraction. Methods: To understand the molecular mechanisms underlying the cocaine response in the CV system, we studied the role of miRNA-423-5p and its target Cacna2d2 in the regulation of intracellular calcium concentration and SMC contractility, a critical factor in the modulation of blood pressure (BP). We used in vivo models to evaluate BP and aortic stiffness. Results: In vitro, Cocaine treatment decreased miR-423-5p expression and increased Cacna2d2 expression, which led to elevated intracellular calcium concentrations and increased SMC contractility. Overexpression of miR-423-5p, silencing of its target Cacna2d2, and treatment with a calcium channel blocker reversed the elevated SMC contractility caused by cocaine. In contrast, suppression of miR-423-5p increased the intracellular calcium concentration and SMC contractibility. In vivo, overexpression of miR-423-5p ameliorated the increase in BP and aortic stiffness associated with cocaine use. Conclusions: MiR-423-5p regulates SMC contraction by modulating Cacna2d2 expression increasing intracellular calcium concentrations. Modulation of miR-423-5p—Cacna2d2—Calcium transport pathway may represent a novel therapeutic strategy to improve cocaine-induced hypertension and aortic stiffness.

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“…These sympathomimetic effects led to the stimulation of cardiomyocyte adrenergic receptors, resulting in increased heart rate, BP, and vasoconstriction, which, in turn, increases myocardial oxygen demand. The sympathomimetic effects can cause elevated levels of the vasoconstrictor protein endothelin-1 [ 55 ], increased ROS levels [ 33 ], inhibited nitric oxide (NO) synthase [ 21 ], impaired acetylcholine-induced vasorelaxation [ 56 ], and dysregulated intracellular calcium levels [ 57 ]. Although the sympathomimetic mechanisms contribute to CV disorders, they cannot explain the full extent and the diversity of cocaine-induced CV phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…By modulating Cacna2d2 expression, miR-423-5p was found to control [Ca 2+ ]i and, in turn, SMC contractility. It is well established that the regulation of [Ca 2+ ]i levels plays a critical role in regulating SMC contractility and the development of myocardial ischemia, infarction, HTN, and arrhythmia [ 20 , 48 , 57 , 66 ]. L-type Cav1.2 channels (LTCCs) are the principal channels involved in mediating the influx of Ca 2+ and the regulation of myogenic tone [ 45 , 46 , 47 ] .…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-423-5p Mediates Cocaine-Induced Smooth Muscle Cell Contraction by Targeting Cacna2d2

Dykxhoorn

Wang

Ferreira

et al. 2023

IJMS

View full text Add to dashboard Cite

Cocaine abuse increases the risk of atherosclerotic cardiovascular disease (CVD) and causes acute coronary syndromes (ACS) and hypertension (HTN). Significant research has explored the role of the sympathetic nervous system mediating the cocaine effects on the cardiovascular (CV) system. However, the response of the sympathetic nervous system alone is insufficient to completely account for the CV consequences seen in cocaine users. In this study, we examined the role of microRNAs (miRNAs) in mediating the effect of cocaine on the CV system. MiRNAs regulate many important biological processes and have been associated with both response to cocaine and CV disease development. Multiple miRNAs have altered expression in the CV system (CVS) upon cocaine exposure. To understand the molecular mechanisms underlying the cocaine response in the CV system, we studied the role of miRNA-423-5p and its target Cacna2d2 in the regulation of intracellular calcium concentration and SMC contractility, a critical factor in the modulation of blood pressure (BP). We used in vivo models to evaluate BP and aortic stiffness. In vitro, cocaine treatment decreased miR-423-5p expression and increased Cacna2d2 expression, which led to elevated intracellular calcium concentrations and increased SMC contractility. Overexpression of miR-423-5p, silencing of its target Cacna2d2, and treatment with a calcium channel blocker reversed the elevated SMC contractility caused by cocaine. In contrast, suppression of miR-423-5p increased the intracellular calcium concentration and SMC contractibility. In vivo, smooth muscle-specific overexpression of miR-423-5p ameliorated the increase in BP and aortic stiffness associated with cocaine use. Thus, miR-423-5p regulates SMC contraction by modulating Cacna2d2 expression increasing intracellular calcium concentrations. Modulation of the miR-423-5p—Cacna2d2—Calcium transport pathway may represent a novel therapeutic strategy to improve cocaine-induced HTN and aortic stiffness.

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Effects of Cocaine on Intracellular Calcium Handling In Cardiac and Vascular Smooth Muscle

Cited by 5 publications

References 0 publications

Acute and Chronic Effects of Cocaine on Cardiovascular Health

Acute and Chronic Effects of Cocaine on Cardiovascular Health

MicroRNA-423-5p Mediates Cocaine-Induced Smooth Muscle Cell Contraction by Targeting Cacna2d2

MicroRNA-423-5p Mediates Cocaine-Induced Smooth Muscle Cell Contraction by Targeting Cacna2d2

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