Impact of MicroRNA‐21 Knockout on Coronary Collateral Growth in Metabolic Syndrome

Abstract

A highly‐functional coronary collateral circulation proves beneficial during acute coronary occlusions such as myocardial infarctions, but the molecular drivers of coronary collateral growth (CCG) have yet to be completely understood. Our previous work shows that CCG is impaired in Zucker Obese Fatty (ZOF) rats (a rat model of metabolic syndrome). These results are consistent with what is seen in human patients with metabolic syndrome. Our gene expression profiling of rat hearts during repetitive ischemia (RI) in ZOF rats and Zucker lean (ZLN) rats showed microRNA‐21 (miR‐21) to be one of the most upregulated genes, and was found to be significantly increased in ZOF rat hearts compared to ZLN rat hearts. This expression was also validated by quantitative RT‐PCR. Interestingly, miR‐21 was reported to play a critical role during CCG in a JCR rats (another rat model of metabolic syndrome) where treatment with a miR‐21 antagomir improved RI‐induced CCG. Since miR‐21 antagomirs may target any metabolically active tissue such as liver, intestine and heart, it is unknown how the knockdown of miR‐21 ameliorate CCG. The miR‐21 knockout (KO) mouse will help us to investigate this question. First, we mapped out where miR‐21 expression occurs by LacZ staining in a miR‐21 mice with a LacZ gene knockin. Staining has shown that there is an abundance of miR‐21 expressed in the heart, aorta, and muscle vasculature of mice. We then investigated the impact that genetic ablation of miR‐21 has on coronary collateral formation in a mouse model of metabolic syndrome induced by a high fat high sugar (HFHS) diet. A pneumatic balloon is surgically placed over the left anterior descending artery (LAD), and after a recovery period the mice underwent RI protocol. CCG was measured by myocardial blood flow with contrast echocardiography and by collateral numbers using micro‐computed tomography (microCT). Interestingly, the right coronary artery (RCA) of miR‐21 KO mice were poorly perfused, possibly suggesting miR‐21 is a player in coronary artery development or potentially in the development of atherosclerotic lesions. Impaired CCG of mice on HFHS diet was restored by miR‐21 KO. Moreover, miR‐21 expression levels were increased in induced vascular progenitor and endothelial cells subjected to high fat and high glucose treatment. miR‐21 expression was also increased in diabetic (db/db) and obese (ob/ob) mice. These data suggest that miR‐21 is a key player in the cardiovascular system in metabolic syndrome and is likely to be involved in the impairment of CCG in metabolic syndrome.Support or Funding InformationThe research is funded by National Institutes of Health grant 2R01HL103227‐05( Zhang, Yin), 1R01HL135110‐01 (WMC, LY), 1 R01 HL137008‐01A1 (LY), 1R15HL115540‐01 (LY) and 14BGIA18770028 from American Heart Association.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.