Myeloid Derived miR‐21 Influences Coronary Collateral Growth in Metabolic Syndrome

Abstract

Well‐developed coronary collaterals prove to be highly beneficial in salvaging ischemic myocardium, preserving cardiac function, and improving patient outcome post‐occlusion. However, this process is impaired in patients with metabolic syndrome. A more complete understanding of the underlying mechanism, cell types, and genes causing the impaired coronary collateral growth (CCG) response have yet to be elucidated. Better understanding of the process of CCG will lead to potential therapeutics to induce CCG and circumvent ischemic injury. MicroRNA‐21 (miR‐21) has been studied in cancer, with its central role in the down‐regulation of pro‐apoptotic genes leading to sustained cellular proliferation. However, miR‐21 has recently been reported to modulate inflammation after myocardial infarction (MI) and to play a role in the development of atherosclerosis. Furthermore, miR‐21 has been shown to be involved in macrophage polarization, where it generally serves to reduce inflammatory markers and promote anti‐inflammatory markers. In addition, miR‐21 dysregulation has been rooted in the diabetic population wherein lies a systemic inflammatory state. In this study, we investigated the role of miR‐21 during CCG in diabetes mellitus, which is a major risk factor for the development of cardiovascular disease. Our preliminary data suggested that down‐regulating miR‐21 rescues the impaired CCG in diet‐induced diabetic animals. Given that miR‐21 is highly abundant in immune cells, we sought to further study if miR‐21 regulates CCG by modulating the inflammatory response. While macrophages have been extensively studied during MI events or in atherosclerosis conditions, their roles during CCG are not well‐defined. Thus, we utilize a myeloid specific (Lyz2) miR‐21 knockout to investigate the impact of miR‐21 in macrophages on CCG within the context of diabetes. First, colony stimulating factor‐1 directed bone marrow derived macrophages from miR‐21 Lyz2‐knockout mice were subjected to high glucose (4.5 g/L) and / or hypoxia (3% oxygen) to mimic diabetic conditions. Interestingly, the knockout macrophages have differences in their spindle like projections even before beginning treatment. This possibly suggests greater baseline activation compared to the control. We also observe morphological differences after treatment. The expression profile will give more accurate results. In vivo, CCG is blunted in the miR‐21 Lyz2‐knockout animals subjected to the repetitive ischemia protocol. This suggests that miR‐21 in the myeloid lineage is critical for CCG in healthy non‐diabetic mice. Further studies of CCG in the miR‐21 Lyz2‐knockout mice fed high fat and high sugar diet will give us more insight into the mechanisms underlying impaired CCG in diabetes.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 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.