Journal Article

miR‐29 contributes to normal endothelial function and can restore it in cardiometabolic disorders

Liu, Pengyuan, Tyagi, Sudhi, Zhang, Guangyuan, Chu, Chen, Usa, Kristie, Malik, Mobin, Geurts, Aron M, Branum, Amberly, Kriegel, Alison J, Ying, Rong, Jensen, David M, Wang, Jingli, Widlansky, Michael E, Tanner, Michael J, Liu, Yong, Casati, Marc, Liang, Mingyu

2018

Overview

We investigated the role of microRNAs (miRNA) in endothelial dysfunction in the setting of cardiometabolic disorders represented by type 2 diabetes mellitus (T2DM). miR‐29 was dysregulated in resistance arterioles obtained by biopsy in T2DM patients. Intraluminal delivery of miR‐29a‐3p or miR‐29b‐3p mimics restored normal endothelium‐dependent vasodilation (EDVD) in T2DM arterioles that otherwise exhibited impaired EDVD. Intraluminal delivery of anti‐miR‐29b‐3p in arterioles from non‐DM human subjects or rats or targeted mutation of Mir29b‐1/a gene in rats led to impaired EDVD and exacerbation of hypertension in the rats. miR‐29b‐3p mimic increased, while anti‐miR‐29b‐3p or Mir29b‐1/a gene mutation decreased, nitric oxide levels in arterioles. The mutation of Mir29b‐1/a gene led to preferential differential expression of genes related to nitric oxide including Lypla1. Lypla1 was a direct target of miR‐29 and could abrogate the effect of miR‐29 in promoting nitric oxide production. Treatment with Lypla1 siRNA improved EDVD in arterioles obtained from T2DM patients or Mir29b‐1/a mutant rats or treated with anti‐miR‐29b‐3p. These findings indicate miR‐29 is required for normal endothelial function in humans and animal models and has therapeutic potential for cardiometabolic disorders. Synopsis Administration of miR‐29 restores endothelium‐dependent vasodilation in arterioles from humans with cardiometabolic disorders, and endogenous miR‐29 is required for normal endothelial function in human and rat arterioles and blunts the development of hypertension in rats. microRNA expression profiles in resistance arterioles are altered in patients with cardiometabolic disorders represented by type 2 diabetes (T2DM). miR‐29 restores endothelium‐dependent vasodilation in resistance arterioles obtained from T2DM patients that otherwise exhibit endothelial dysfunction. miR‐29 is required for normal endothelial function in human and rat arterioles. miR‐29 insufficiencies exacerbate hypertension in rats. miR‐29 preferentially influenced the expression of genes relevant to the regulation of NO bioavailability in arterioles. Targeting of Lysophospholipase I (Lypla1) contributes to the effect of miR‐29 in promoting nitric oxide (NO) generation and endothelium‐dependent vasodilation. Graphical Abstract Administration of miR‐29 restores endothelium‐dependent vasodilation in arterioles from humans with cardiometabolic disorders, and endogenous miR‐29 is required for normal endothelial function in human and rat arterioles and blunts the development of hypertension in rats.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Adult / Aged / Animal models / Animals / Arterioles / Arterioles - metabolism / Arterioles - pathology / Arterioles - physiopathology / Bioavailability / Biopsy / Cardiovascular Diseases - genetics / Cardiovascular Diseases - pathology / Cardiovascular Diseases - physiopathology / Circulatory system / Diabetes / Diabetes mellitus / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - genetics / Disease Models, Animal / EMBO21 / EMBO46 / Endothelium / Endothelium, Vascular - metabolism / Endothelium, Vascular - pathology / Endothelium, Vascular - physiopathology / Gene Expression Regulation / Gene regulation / Genes / Humans / Hypertension / Lysophospholipase / microRNA / MicroRNAs - genetics / MicroRNAs - metabolism / Middle Aged / miRNA / Mutation / Nitric oxide / Nitric Oxide - metabolism / Point mutation / Rats / Recovery of function / Research Article / Rodents / siRNA / Vascular Resistance / Vasodilation