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

Abstract

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.

Clinical significance of circulating microRNAs as diagnostic biomarkers for coronary artery disease

“…miR‐29a remarkably improves the endothelial function in human T2DM arterioles and facilitates the restoration of endothelium‐dependent vasodilation in resistance arterioles . miR‐29a negatively regulates the expression of myeloid cell leukaemia 1 (MCL‐1), a prosurvival protein indispensable for the survival and function of cardiomyocytes and VSMCs .…”

“…miRNAs are key regulators in the function of cardiomyocytes, endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and platelets which involve in the initiation and progression of atherosclerosis—the main cause of CAD. miR‐29a is required for normal function of endothelial cells and can restore it in cardiometabolic disorders . miR‐29a also takes part in the survival and function maintenance of cardiomyocytes .…”

Plasma levels of miR‐29b and miR‐200b in type 2 diabetic retinopathy

“…14 However, these findings contrast with studies that reported either higher circulating levels of miR-29 in subjects with prediabetes 37 and type 2 diabetes 35,37 or lower miR-29b levels in those with prediabetes 38 and who developed type 2 diabetes in the prospective population-based Bruneck study. 39 It is tempting to speculate whether miR-29b is up-regulated in type 2 diabetes as a failed attempt to compensate for the endothelial dysfunction, as 27 The authors showed that miR-29 is required for normal endothelial function and can restore it in cardiometabolic disorders. 27 In addition, evidence obtained in knockout mice revealed that the miR-29 family has a protective role in beta cells and a pathogenic function in the liver.…”

“…39 It is tempting to speculate whether miR-29b is up-regulated in type 2 diabetes as a failed attempt to compensate for the endothelial dysfunction, as 27 The authors showed that miR-29 is required for normal endothelial function and can restore it in cardiometabolic disorders. 27 In addition, evidence obtained in knockout mice revealed that the miR-29 family has a protective role in beta cells and a pathogenic function in the liver. 40 Paradoxically, increased miR-29 expression was reported to lead to increased insulin resistance, and decreased insulin secretion and signaling in metabolic tissues.…”

“…8,[12][13][14] Despite this, the profile of circulating miRNAs in DR has been evaluated only recently. [15][16][17][18][19][20][21][22][23][24][25] MiR-29b and miR-200b were one of the first miRNAs found to be dysregulated in high glucose-exposed retinal cells and diabetic murines, thereby suggesting their involvement in the development of DR. MiR-29b exerts anti-apoptotic and antifibrotic effects on retinal cells 12,26 and contributes to endothelial function by increasing nitric oxide, 27 while miR-200b protects against vascular permeability and angiogenesis. Down-regulation of miR-29b results in increased matrix deposition and retinal fibrosis, whereas down-regulation of miR-200b results in increased inflammation.…”