SOX2-mediated inhibition of miR-223 contributes to STIM1 activation in phenylephrine-induced hypertrophic cardiomyocytes

Abstract

Stromal interaction molecule 1 (STIM1) is the key molecule responsible for store-operated Ca entry (SOCE). Numerous studies have demonstrated that STIM1 levels appeared to be enhanced during cardiac hypertrophy. However, the mechanism underlining this process remains to be clarified. In this study, phenylephrine (PE) was employed to establish a model of hypertrophic neonatal rat cardiomyocytes (HNRCs) in vitro, and low expression of primary and mature miR-223 was detected in PE-induced HNRCs. Our results have revealed that downregulation of miR-223 by PE contributed to the increase of STIM1, which in turn induced cardiac hypertrophy. As expected, overexpression of miR-223 could prevent the increase in cell surface and reduce the mRNA levels of ANF and BNP in cardiomyocytes. To address the mechanism triggering downregulation of miR-223 under PE, we demonstrated that PE-induced inhibition of GSK-3β activity led to the activation of β-catenin, which initiates the transcription of SOX2. Increased expression of SOX2 occupied the promoter region of primary miR-223 and suppressed its transcription. Therefore, miR-223 appears to be a promising candidate for inhibiting cardiomyocyte hypertrophy, and miR-223/STIM1 axis might be one of interesting targets for the clinical treatment of hypertrophy.

miRNA-dependent regulation of STIM1 expression in breast cancer

“…miRNAs have been implicated in regulating SOCE in different tissues. STIM1 expression has been shown to be regulated by miR-195 in intestinal epithelial cells (miR-195) 21 ; miR-424 in vascular smooth muscle 31 ; miR-185 in colorectal cancer 10 , and miR-223 in cardiac hypertrophy 32 and glioblastomas 33 .…”

MiR-223-3p in Cardiovascular Diseases: A Biomarker and Potential Therapeutic Target

“…Current researches have demonstrated that miR-223-3p has biphasic effects on heart failure through bidirectional regulation of cardiac hypertrophy and promotion of inflammatory response. Both in the rat model of cardiac hypertrophy induced by transverse aorta constriction and in hypertrophic cardiomyocyte models treated with different inducing reagents endothelin-1 or phenylephrine, the expression of miR-223-3p in myocardium and cardiomyocytes were downregulated (124,125). The mechanism underlying the phenylephrineinduced downregulation of miR-223-3p in cardiomyocytes was suppressing glycogen synthase kinase 3 β activity to reduce β-catenin degradation and increase its activation (125).…”

“…Both in the rat model of cardiac hypertrophy induced by transverse aorta constriction and in hypertrophic cardiomyocyte models treated with different inducing reagents endothelin-1 or phenylephrine, the expression of miR-223-3p in myocardium and cardiomyocytes were downregulated (124,125). The mechanism underlying the phenylephrineinduced downregulation of miR-223-3p in cardiomyocytes was suppressing glycogen synthase kinase 3 β activity to reduce β-catenin degradation and increase its activation (125). This modulation upregulated SRY-box transcription factor 2, which could promote cardiomyocytes proliferation and increase heart size, to inhibit the transcription of primary miR-223 (125,126).…”

“…The mechanism underlying the phenylephrineinduced downregulation of miR-223-3p in cardiomyocytes was suppressing glycogen synthase kinase 3 β activity to reduce β-catenin degradation and increase its activation (125). This modulation upregulated SRY-box transcription factor 2, which could promote cardiomyocytes proliferation and increase heart size, to inhibit the transcription of primary miR-223 (125,126). Inhibition of primary miR-223 increased the stromal interaction molecule 1 (STIM1), a target of miR-223-3p, to induce cardiomyocyte hypertrophy through elevating the cytosolic Ca 2+ levels of cardiomyocytes (125,(127)(128)(129).…”

“…This modulation upregulated SRY-box transcription factor 2, which could promote cardiomyocytes proliferation and increase heart size, to inhibit the transcription of primary miR-223 (125,126). Inhibition of primary miR-223 increased the stromal interaction molecule 1 (STIM1), a target of miR-223-3p, to induce cardiomyocyte hypertrophy through elevating the cytosolic Ca 2+ levels of cardiomyocytes (125,(127)(128)(129). When overexpressing miR-223-3p or miR-223(-3p/5p) in cardiomyocytes, the hypertrophy was ameliorated mainly manifesting as smaller cellular surface area, downregulation of classic pathological hypertrophy marker genes encoding atrial natriuretic peptide (ANP), B type natriuretic peptide (BNP), α-actinin, and myosin heavy chain 6/7 (MYH6/7) (124,125).…”