MicroRNA-19a/b-3p protect the heart from hypertension-induced pathological cardiac hypertrophy through PDE5A

Abstract

Aim:PDE5A is a leading factor contributing to cGMP signaling and cardiac hypertrophy. However, microRNA-mediated posttranscriptional regulation of PDE5A has not been reported. The aim of this study is to screen the microRNAs that are able to regulate PDE5A and explore the function of the microRNAs in cardiac hypertrophy and remodeling.Methods and Results:Although miR-19a/b-3p (microRNA-19a-3p and microRNA-19b-3p) have been reported to be differentially expressed during cardiac hypertrophy, the direct targets and the functions of this microRNA family for regulation of cardiac hypertrophy have not yet been investigated. The present study identified some direct targets and the underlying functions of miR-19a/b-3p by using bioinformatics tools and gene manipulations within mouse neonatal cardiomyocytes. Transfection of miR-19a/b-3p down-regulated endogenous expressions of PDE5A at both mRNA and protein levels with real-time PCR and western blot. Luciferase reporter assays showed that PDE5A was a direct target of miR-19a/b-3p. In mouse models of cardiac hypertrophy, we found that miR-19a/b-3p was expressed in cardiomyocytes and that its expression was reduced in pressure overload-induced hypertrophic hearts. miR-19a/b-3p transgenic mice prevented the progress of cardiac hypertrophy and cardiac remodeling in response to angiotensin II infusion with echocardiographic assessment and pressure–volume relation analysis.Conclusion:Our study elucidates that PDE5A is a novel direct target of miR-19a/b-3p, and demonstrates that antihypertrophic roles of the miR-19a/b-3p family in Ang II-induced hypertrophy and cardiac remodeling, suggests that endogenous miR-19a/b-3p might have clinical potential to suppress cardiac hypertrophy and heart failure.

Human umbilical cord mesenchymal stem cells-derived exosomes transfers microRNA-19a to protect cardiomyocytes from acute myocardial infarction by targeting SOX6

“…A striking demonstration supported that miR-19a/ b family could promote proliferation and survival of ischemic neural progenitor cells and primary cardiomyocytes, and revealed the potential capability of miR-19a/b in cardiac repair and regeneration [32]. Besides, miR-19a-3p was also evaluated to inhibit cardiac hypertrophy, cardiac remodeling and heart failure [33]. Importantly, Gao et al have stated that overexpression of miR-19a/19b substantially diminished Cleaved caspase3 levels and inflammation, preserved cardiac function and reduced infarct size, thus showing therapeutic roles in cardiac regeneration and protection from myocardial infarction [20].…”

Inhibited histone deacetylase 3 ameliorates myocardial ischemia–reperfusion injury in a rat model by elevating microRNA‐19a‐3p and reducing cyclin‐dependent kinase 2

“…HDAC3 is a major histone deacetylase, and its enzyme activity is the target of small molecule inhibitors in the treatment of various diseases 21 . Studies have shown that HDAC3 expression is downregulated in ischemic myocardial injury 22 and hypertrophic cardiomyocytes 12,23 . CDK2 also plays an important role in the regulation of apoptosis in MIRI 15 .…”

“…21 Studies have shown that HDAC3 expression is downregulated in ischemic myocardial injury 22 and hypertrophic cardiomyocytes. 12,23 CDK2 also plays an important role in the regulation of apoptosis in MIRI. 15 In order to further study the effects of mir-19a-3p, HDAC3, and CDK2 on MIRI, we detected their expression in rat myocardial tissues using RT-qPCR and Western blot analysis.…”

Relationship between miR-92b expression and hypertension, the degree of heart disease and cerebral hemorrhage

“…There are multiple mechanisms for the progression of hypertension to HTN-LVH, heart failure or cerebral hemorrhage. For instance, miR-19a/b-3p defenses the heart from pathological myocardial hypertrophy induced by hypertension via targeting PDE5A [15]. Up-regulated miR-133 can attenuate agonist-induced cell hypertrophy [16], balk myocardial brosis [17], and modulate heart development and normal heart function.…”