Lack of miR-133a Decreases Contractility of Diabetic Hearts: A Role for Novel Cross Talk Between Tyrosine Aminotransferase and Tyrosine Hydroxylase

Abstract

MicroRNAs (miRNAs) have a fundamental role in diabetic heart failure. The cardioprotective miRNA-133a (miR-133a) is downregulated, and contractility is decreased in diabetic hearts. Norepinephrine (NE) is a key catecholamine that stimulates contractility by activating β-adrenergic receptors (β-AR). NE is synthesized from tyrosine by the rate-limiting enzyme, tyrosine hydroxylase (TH), and tyrosine is catabolized by tyrosine aminotransferase (TAT). However, the cross talk/link between TAT and TH in the heart is unclear. To determine whether miR-133a plays a role in the cross talk between TH and TAT and regulates contractility by influencing NE biosynthesis and/or β-AR levels in diabetic hearts, Sprague-Dawley rats and miR-133a transgenic (miR-133aTg) mice were injected with streptozotocin to induce diabetes. The diabetic rats were then treated with miR-133a mimic or scrambled miRNA. Our results revealed that miR-133a mimic treatment improved the contractility of the diabetic rat’s heart concomitant with upregulation of TH, cardiac NE, β-AR, and downregulation of TAT and plasma levels of NE. In miR-133aTg mice, cardiac-specific miR-133a overexpression prevented upregulation of TAT and suppression of TH in the heart after streptozotocin was administered. Moreover, miR-133a overexpression in CATH.a neuronal cells suppressed TAT with concomitant upregulation of TH, whereas knockdown and overexpression of TAT demonstrated that TAT inhibited TH. Luciferase reporter assay confirmed that miR-133a targets TAT. In conclusion, miR-133a controls the contractility of diabetic hearts by targeting TAT, regulating NE biosynthesis, and consequently, β-AR and cardiac function.

MMP9 mediates acute hyperglycemia-induced human cardiac stem cell death by upregulating apoptosis and pyroptosis in vitro

“…Cardiomyocytes obtained from MMP9 −/− mice have a robust increase in the levels of miR-133a 9 , an anti-hypertrophy 35 and anti-fibrosis 36 miRNA, which is decreased in the diabetic heart 37 . Increasing miR-133a in the DM heart improves cardiac contractility 38 and functions 39 , and prevents DM-induced metabolic remodeling 40 . MiRNA overexpression in the stem cell improves their survival and cardiac regeneration capacity 41,42 .…”

H2S and homocysteine control a novel feedback regulation of cystathionine beta synthase and cystathionine gamma lyase in cardiomyocytes

“…The purity and quantity of RNA was measured by NanoDrop 2000c (Thermo Scientific Inc., USA), and good quality RNA was used for miR-133a assay as described elsewhere 19 .…”

Diabetic Cardiomyopathy: An Immunometabolic Perspective

“…Murine miR-322 has recently been shown to provide cardioprotection against consequences of hyperinsulinemia and hyperlipidemia (188). In Ins+/– Akita mice, a model for T1DM, the majority of miRNAs are downregulated in the heart (189), including miR-133a which regulates contractility of the diabetic heart (190). Even after treatment with insulin, which normalizes blood glucose levels, there are several miRNAs that remain differentially regulated in the diabetic heart, and they can potentially contribute to pathological remodeling of the diabetic heart (191).…”

“…MiR-133a, the most abundant miRNA in the heart, is downregulated in the diabetic mice heart with consequent induction of cardiac hypertrophy (202) and fibrosis (187). Lack of miR-133a also causes contractile dysfunction in the diabetic mice heart (190). These changes cause diastolic dysfunction, which if untreated leads to potential systolic dysfunction (28).…”