Cocaine exposure increases blood pressure and aortic stiffness via the mir-30c-5p-malic enzyme 1-reactive oxygen species pathway

Wei Zhu, Huilan Wang, Jianqin Wei, Gregory Sartor, Michelle Meiqi Bao, Clay T. Pierce, Claes R Wahlestedt, Derek M Dykxhoorn, Chunming Dong

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Cocaine abuse increases the risk of cardiovascular mortality and morbidity; however, the underlying molecular mechanisms remain elusive. By using a mouse model for cocaine abuse/use, we found that repeated cocaine injection led to increased blood pressure and aortic stiffness in mice associated with elevated levels of reactive oxygen species (ROS) in the aortas, a phenomenon similar to that observed in hypertensive humans. This ROS elevation was correlated with downregulation of Me1 (malic enzyme 1), an important redox molecule that counteracts ROS generation, and upregulation of microRNA (miR)-30c-5p that targets Me1 expression by directly binding to its 3'UTR (untranslated region). Remarkably, lentivirus-mediated overexpression of miR-30c-5p in aortic smooth muscle cells recapitulated the effect of cocaine on Me1 suppression, which in turn led to ROS elevation. Moreover, in vivo silencing of miR-30c-5p in smooth muscle cells resulted in Me1 upregulation, ROS reduction, and significantly suppressed cocaine-induced increases in blood pressure and aortic stiffness-a similar effect to that produced by treatment with the antioxidant N-acetyl cysteine. Discovery of this novel cocaine-?miR-30c-5p-?Me1-?ROS pathway provides a potential new therapeutic avenue for treatment of cocaine abuse-related cardiovascular disease.

Original languageEnglish (US)
Pages (from-to)752-760
Number of pages9
JournalHypertension
Volume71
Issue number4
DOIs
StatePublished - Jan 1 2018

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malate dehydrogenase (decarboxylating)
Vascular Stiffness
Cocaine
Reactive Oxygen Species
Blood Pressure
MicroRNAs
Cocaine-Related Disorders
3' Untranslated Regions
Smooth Muscle Myocytes
Up-Regulation
Lentivirus
Oxidation-Reduction
Cysteine
Aorta
Cardiovascular Diseases
Therapeutics
Down-Regulation
Antioxidants
Morbidity
Injections

Keywords

  • Antioxidant
  • Blood pressure
  • Cocaine
  • microRNA
  • Reactive oxygen species

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Cocaine exposure increases blood pressure and aortic stiffness via the mir-30c-5p-malic enzyme 1-reactive oxygen species pathway. / Zhu, Wei; Wang, Huilan; Wei, Jianqin; Sartor, Gregory; Bao, Michelle Meiqi; Pierce, Clay T.; Wahlestedt, Claes R; Dykxhoorn, Derek M; Dong, Chunming.

In: Hypertension, Vol. 71, No. 4, 01.01.2018, p. 752-760.

Research output: Contribution to journalArticle

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abstract = "Cocaine abuse increases the risk of cardiovascular mortality and morbidity; however, the underlying molecular mechanisms remain elusive. By using a mouse model for cocaine abuse/use, we found that repeated cocaine injection led to increased blood pressure and aortic stiffness in mice associated with elevated levels of reactive oxygen species (ROS) in the aortas, a phenomenon similar to that observed in hypertensive humans. This ROS elevation was correlated with downregulation of Me1 (malic enzyme 1), an important redox molecule that counteracts ROS generation, and upregulation of microRNA (miR)-30c-5p that targets Me1 expression by directly binding to its 3'UTR (untranslated region). Remarkably, lentivirus-mediated overexpression of miR-30c-5p in aortic smooth muscle cells recapitulated the effect of cocaine on Me1 suppression, which in turn led to ROS elevation. Moreover, in vivo silencing of miR-30c-5p in smooth muscle cells resulted in Me1 upregulation, ROS reduction, and significantly suppressed cocaine-induced increases in blood pressure and aortic stiffness-a similar effect to that produced by treatment with the antioxidant N-acetyl cysteine. Discovery of this novel cocaine-?miR-30c-5p-?Me1-?ROS pathway provides a potential new therapeutic avenue for treatment of cocaine abuse-related cardiovascular disease.",
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