The miRNA199a/SIRT1/P300/Yy1/sST2 signaling axis regulates adverse cardiac remodeling following MI

Abstract

Left ventricular remodeling following myocardial infarction (MI) is related to adverse outcome. It has been shown that an up-regulation of plasma soluble ST2 (sST2) levels are associated with lower pre-discharge left ventricular (LV) ejection fraction, adverse cardiovascular outcomes and mortality outcome after MI. The mechanisms involved in its modulation are unknown and there is not specific treatment capable of lowering plasma sST2 levels in acute-stage HF. We recently identified Yin-yang 1 (Yy1) as a transcription factor related to circulating soluble ST2 isoform (sST2) expression in infarcted myocardium. However, the underlying mechanisms involved in this process have not been thoroughly elucidated. This study aimed to evaluate the pathophysiological implication of miR-199a-5p in cardiac remodeling and the expression of the soluble ST2 isoform. Myocardial infarction (MI) was induced by permanent ligation of the left anterior coronary artery in C57BL6/J mice that randomly received antimiR199a therapy, antimiR-Ctrl or saline. A model of biomechanical stretching was also used to characterize the underlying mechanisms involved in the activation of Yy1/sST2 axis. Our results show that the significant upregulation of miR-199a-5p after myocardial infarction increases pathological cardiac hypertrophy by upregulating circulating soluble sST2 levels. AntimiR199a therapy up-regulates Sirt1 and inactivates the co-activator P300 protein, thus leading to Yy1 inhibition which decreases both expression and release of circulating sST2 by cardiomyocytes after myocardial infarction. Pharmacological inhibition of miR-199a rescues cardiac hypertrophy and heart failure in mice, offering a potential therapeutic approach for cardiac failure.

Advances in research on molecular markers in immune checkpoint inhibitor‐associated myocarditis

“…Plasma sST2 levels were positively correlated with cTnI and NT-proBNP and negatively correlated with cardiac systolic function. These findings further support the utility of sST2 as a diagnostic molecular marker for ICIAM, with higher levels indicating increased myocardial fibrosis and poor cardiac remodeling [67,68]. Meanwhile, sST2 has a significant independent predictive value for the prognosis of ICIAM patients [69,70].…”

AEOL-Induced NRF2 Activation and DWORF Overexpression Mitigate Myocardial I/R Injury

“…Measurement of circulating sST2. Plasma samples isolated from mice 24 h after mI/R were assayed for sST2 levels, as previously described 33 using an ELISA kit (Quantikine ELISA Mouse ST2/IL33R (MST200); R&D Systems, USA). Measurement at 24 h post-mI/R was based on a previous study showing an increase in circulating sST2 in acute-phase injury 33 .…”

“…Plasma samples isolated from mice 24 h after mI/R were assayed for sST2 levels, as previously described 33 using an ELISA kit (Quantikine ELISA Mouse ST2/IL33R (MST200); R&D Systems, USA). Measurement at 24 h post-mI/R was based on a previous study showing an increase in circulating sST2 in acute-phase injury 33 . Reactions were terminated by addition of a stop solution, and absorbance was determined at 450 nm in a Clariostar microplate reader (BMG Labtech).…”

Interaction between SIRT1 and non-coding RNAs in different disorders

“…For instance, downregulation of miR-22 by targeting SIRT1/PGC-1α could alleviate this disorder ( Wang et al, 2021b ). Finally, miR199/SIRT1/P300 axis has apotential function in the patheticlogy of this disorder ( Asensio-Lopez et al, 2021 ).…”