miR-410 and miR-495 Are Dynamically Regulated in Diverse Cardiomyopathies and Their Inhibition Attenuates Pathological Hypertrophy

Abstract

Noncoding RNAs have emerged as important modulators in cardiac development and pathological remodeling. Recently, we demonstrated that regulation of the Gtl2-Dio3 noncoding RNA locus is dependent on the MEF2 transcription factor in cardiac muscle, and that two of its encoded miRNAs, miR-410 and miR-495, induce robust cardiomyocyte proliferation. Given the possibility of manipulating the expression of these miRNAs to repair the damaged heart by stimulating cardiomyocyte proliferation, it is important to determine whether the Gtl2-Dio3 noncoding RNAs are regulated in cardiac disease and whether they function downstream of pathological cardiac stress signaling. Therefore, we examined expression of the above miRNAs processed from the Gtl2-Dio3 locus in various cardiomyopathies. These noncoding RNAs were upregulated in all cardiac disease models examined including myocardial infarction (MI) and chronic angiotensin II (Ang II) stimulation, and in the cardiomyopathies associated with muscular dystrophies. Consistent with these observations, we show that the Gtl2-Dio3 proximal promoter is activated by stress stimuli in cardiomyocytes and requires MEF2 for its induction. Furthermore, inhibiting miR-410 or miR-495 in stressed cardiomyocytes attenuated the hypertrophic response. Thus, the Gtl2-Dio3 noncoding RNA locus is a novel marker of cardiac disease and modulating the activity of its encoded miRNAs may mitigate pathological cardiac remodeling in these diseases.

Inhibition of miR-495 Improves Both Vascular Remodeling and Angiogenesis in Pulmonary Hypertension

“…Although right heart hypertrophy index in our experiment has been reduced, probably due to the decline of pulmonary arterial pressure, we cannot exclude a direct role for miR-495 in the cardiac hypertrophic processes implicated in PH. After all, miR-495 was previously described as a prohypertrophic molecule in regulating cardiomyocyte stress signaling in various pathological cardiac remodeling models [27, 28]. …”

Attenuation of MicroRNA-495 Derepressed PTEN to Effectively Protect Rat Cardiomyocytes from Hypertrophy

“…However, the role of miRNAs in the adaptation of the RV to pressure and volume overload and the transition to RV failure remains unclear. We focused on miR-495 in right heart hypertrophy for the following reasons: (1) miR-495 was initially identified as one of the deregulated miRNAs in the Gtl2-Dio3 locus; (2) miR-495 is upregulated in multiple models of cardiac disease and is associated with prohypertrophy; its inhibition in stressed cardiomyocytes thus attenuates the pathological growth response [17]; and (3) the Gtl2-Dio3 locus is also regulated by myocyte enhancer factor 2 (MEF2) in cardiac muscle [15,17]. MEF2 has been implicated in RV development, regulating the metabolic, contractile, and angiogenic genes [25][26][27].…”

“…miR-495 was able to induce the proliferation of neonatal cardiomyocytes in vitro [15]. It was also upregulated as prohypertrophic molecules in multiple models of cardiac diseases [17]. Therefore, we hypothesized that miR-495 plays an important role in RV hypertrophy, and we were interested in examining the function and underlying mechanisms of miR-495 in the development of RV hypertrophy.…”

Relaxin Family Member Insulin‐Like Peptide 6 Ameliorates Cardiac Fibrosis and Prevents Cardiac Remodeling in Murine Heart Failure Models

“…The control group received same amount of sterile saline. The angiotensin II (AngII)–induced cardiac injury model was performed, as previously reported 26, 27, 28, 29, 30, 31. Human AngII protein (A9525; Sigma‐Aldrich) was dissolved with sterile saline.…”