Transgenic Expression of miR-133a in the Diabetic Akita Heart Prevents Cardiac Remodeling and Cardiomyopathy

Abstract

Advanced diabetes mellitus (DM) may have both insulin resistance and deficiency (double DM) that accelerates diabetic cardiomyopathy (DMCM), a cardiac muscle disorder. Reduced cardiac miR-133a, a cardioprotective miRNA, is associated with DMCM. However, it is unclear whether increasing miR-133a levels in the double DM heart could prevent DMCM. We hypothesized that increasing cardiac levels of miR-133a could prevent DMCM in Akita, a mouse model of double DM. To test the hypothesis, we created Akita/miR-133aTg mice, a new strain of Akita where miR-133a is overexpressed in the heart, by crossbreeding male Akita with female cardiac-specific miR-133a transgenic mice. We validated Akita/miR-133aTg mice by genotyping and phenotyping (miR-133a levels in the heart). To determine whether miR-133a overexpression could prevent cardiac remodeling and cardiomyopathy, we evaluated cardiac fibrosis, hypertrophy, and dysfunction (P-V loop) in 13–15 week male WT, Akita, Akita/miR-133aTg, and miR-133aTg mice. Our results revealed that miR-133a overexpression in the Akita heart prevents DM-induced cardiac fibrosis (reduced collagen deposition), hypertrophy (decreased beta-myosin heavy chain), and impaired contractility (downregulated calcium handling protein sarco-endoplasmic reticulum-ATPase-2a). These results demonstrate that increased levels of miR-133a in the DM heart could prevent cardiac remodeling. Our P-V loop analysis showed a trend of decreased cardiac output, stroke volume, and ± dp/dt in Akita, which were blunted in Akita/miR-133aTg heart. These findings suggest that 13–15 week Akita heart undergoes adverse remodeling toward cardiomyopathy, which is prevented by miR-133a overexpression. In addition, increased cardiac miR-133a in the Akita heart did not change blood glucose levels but decreased lipid accumulation in the heart, suggesting inhibition of metabolic remodeling in the heart. Thus, miR-133a could be a promising therapeutic candidate to prevent DMCM.

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 .…”

“…For quantification of intensity of fluorescence, we used NIH Image J software. We followed the previously established protocol for the basic intensity quantification by normalizing mean gray intensity against cell area 40 . The full analyses protocol is available at the following link: https://www.unige.ch/medecine/bioimaging/files/1914/ 1208/6000/Quantification.pdf.…”

SERCA overexpression reduces reperfusion-mediated cardiac microvascular damage through inhibition of the calcium/MCU/mPTP/necroptosis signaling pathways

“…For example, cardiomyocyte repolarization and contractility are handled by SERCA in cardiomyocytes through the Kv channels [ 67 ]. Diabetes-induced cardiac remodeling and cardiomyopathy are also linked to dysregulated SERCA in a manner dependent on the miR-133a [ 68 ]. A recent study reported a novel role for SERCA in preventing hypoxia-related cardiac depression independently of calcium regulation [ 69 ].…”

Diabetes and COVID-19 risk: an miRNA perspective

“…miRNAs involved in these pathways may have important roles in patients with diabetes and COVID-19. Our studies suggest that increasing the cardiac levels of miR-133a in the diabetic heart reduces cardiac lipid accumulation ( 20 ). Thus, miR-133a could regulate lipotoxicity and metabolic remodeling in the diabetic heart.…”