# microRNA Regulation of The Cocaine Effects on the Cardiovascular System

> **NIH VA I01** · MIAMI VA HEALTH CARE SYSTEM · 2023 · —

## Abstract

Despite the opioid overdose crisis, cocaine remains a widely abused illicit drug by the public and
by veterans. While opioid overdose primarily causes respiratory failure, cocaine abuse is mainly
associated with cardiovascular (CV) toxicities, which include hypertension (HTN), aortic stiffness,
and atherosclerosis. Indeed, cocaine abuse represents a significant CV risk for the general
population and for veterans. It is known that cocaine stimulates the sympathetic nervous system
(SNS) by inhibiting norepinephrine (NE) reuptake at nerve terminals; however, recent evidence
suggests that inhibition of NE reuptake may not be the major driver of cocaine-induced HTN. As
such, the mechanisms mediating the effects of cocaine on the CV system remain largely unknown.
To that end, we recently performed small RNA and RNA sequencing in the aortas from mice
treated with cocaine, cocaine methiodide (CM, which does not enter the central nervous system),
or saline to identify potential microRNA (miR)—mRNA pathways that mediate the CV effects of
cocaine. Nine miR—mRNA pathways were implicated. We prioritized and identified two miR-
mRNA axes based on their levels of expression changes and relevance to CV physiology. They
are: 1) the ↑miR-30c—↓Malic Enzyme 1 (ME1)—↑reactive oxygen species (ROS) activity, which
is crucial in HTN and vascular aging (aortic stiffness); and 2) the ↓miR-423—↑Cacna2d2
(encoding the α2δ-2 subunit of voltage-dependent calcium channels) —↑calcium influx resulting
in increased intracellular calcium concentration ([Ca2+]i) which is critical in controlling vascular
smooth muscle cell (SMC) contractility and blood pressure (BP). We thoroughly investigated the
miR-30c pathway and recently published our findings in the journal Hypertension. In preliminary
studies, we showed that cocaine- and CM-induced silencing of miR-423-5p expression and
subsequent upregulation of Cacna2d2 led to increased [Ca2+]i, which augmented contractility in
cultured SMCs. Furthermore, miR-423-5p overexpression ameliorated cocaine-induced BP
elevation in vivo. Interestingly, miR-423-5p has been associated with heart failure and coronary
artery disease. Its role in the pathogenesis of HTN remains unknown. Based on our published
work and preliminary studies, we hypothesize that the miR-423—Cacna2d2 axis plays an
important role in cocaine-induced HTN by regulating calcium influx and intracellular
calcium concentrations ([Ca2+]i) in vascular cells. In addition, recent studies support a strong
crosstalk between these two biological processes—Ca2+ signaling and ROS. We have pilot data
showing that modification of both miR axes largely abrogated cocaine-induced SMC contraction.
Therefore, we further hypothesize that these two pathways work synergistically to mediate
cocaine-induced CV consequences. We will thoroughly characterize the ↓miR-423-5p—
↑Cacna2d2—↑ [Ca2+]i axis and its interaction with the ↑miR-30c—↓ME1—↑ROS pathway in
mediating the effects of cocaine on the CV system...

## Key facts

- **NIH application ID:** 10514596
- **Project number:** 5I01BX004870-03
- **Recipient organization:** MIAMI VA HEALTH CARE SYSTEM
- **Principal Investigator:** CHUNMING DONG
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10514596

## Citation

> US National Institutes of Health, RePORTER application 10514596, microRNA Regulation of The Cocaine Effects on the Cardiovascular System (5I01BX004870-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10514596. Licensed CC0.

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