Downregulation of miR‐128 Ameliorates Ang II‐Induced Cardiac Remodeling via SIRT1/PIK3R1 Multiple Targets

Abstract

Recent studies reported that miR-128 was differentially expressed in cardiomyocytes in response to pathologic stress. However, its function and mechanism remain to be fully elucidated. The aim of the present study was to investigate the role of miR-128 in chronic angiotensin II (Ang II) infusion-induced cardiac remodeling and its underlying mechanism. The cardiac remodeling and heart failure in vivo were established in C57BL/6 mice by chronic subcutaneous Ang II delivery. Knocking down miR-128 was conducted in the hearts of the mice by intravenous injection of HBAAV2/9-miR-128-GFP sponge (miR-128 inhibitor). In vitro experiments of cardiac hypertrophy, apoptosis, and aberrant autophagy were performed in cultured cells after Ang II treatment or transfection of miR-128 antagomir. Our results showed that chronic Ang II delivery for 28 days induced cardiac dysfunction, hypertrophy, fibrosis, apoptosis, and oxidative stress in the mice, while the miR-128 expression was notably enhanced in the left ventricle. Silencing miR-128 in the hearts of mice ameliorated Ang II-induced cardiac dysfunction, hypertrophy, fibrosis apoptosis, and oxidative stress injury. Moreover, Ang II induced excessive autophagy in the mouse hearts, which was suppressed by miR-128 knockdown. In cultured cells, Ang II treatment induced a marked elevation in the miR-128 expression. Downregulation of miR-128 in the cells by transfection with miR-128 antagomir attenuated Ang II-induced apoptosis and oxidative injury probably via directly targeting on the SIRT1/p53 pathway. Intriguingly, we found that miR-128 inhibition activated PIK3R1/Akt/mTOR pathway and thereby significantly damped Ang II-stimulated pathological autophagy in cardiomyocytes, which consequently mitigated cell oxidative stress and apoptosis. In conclusion, downregulation of miR-128 ameliorates Ang II-provoked cardiac oxidative stress, hypertrophy, fibrosis, apoptosis, and dysfunction in mice, likely through targeting on PIK3R1/Akt/mTORC1 and/or SIRT1/p53 pathways. These results indicate that miR-128 inhibition might be a potent therapeutic strategy for maladaptive cardiac remodeling and heart failure.

Impact of Sacubitril/Valsartan on Circulating microRNA in Patients with Heart Failure

“…As a result, these enzymes might also prove valuable as therapeutic targets [ 46 ]. The role of miRNA in the regulation of PI3KR1 was also described in the study by Zhan H. et al [ 47 ], which showed that the downregulation of miR-128 restored PIK3R1 mRNA and the protein levels induced by angiotensin II, being accompanied by upregulation of the levels of phospho-Akt and -mTORC1 in vivo and in vitro. Moreover, alteration of the PIK3R1/Akt/mTORC1 pathway was negatively correlated with autophagy, while mTORC1 blocker rapamycin abolished miR-128 antagomir’s inhibition of angiotensin II-induced apoptosis and ROS production.…”

“…Moreover, alteration of the PIK3R1/Akt/mTORC1 pathway was negatively correlated with autophagy, while mTORC1 blocker rapamycin abolished miR-128 antagomir’s inhibition of angiotensin II-induced apoptosis and ROS production. Therefore, miR-128 downregulation alleviated the angiotensin-II-induced elevation of autophagy, likely via the PIK3R1/Akt/mTORC1 pathway in cardiomyocytes [ 47 ].…”

Therapeutic overexpression of miR-92a-2-5p ameliorated cardiomyocyte oxidative stress injury in the development of diabetic cardiomyopathy

“…Among these selected miRNAs, miR-128-3p has been reported to be involved in the regulation of various heart diseases. The expression of miR-128-3p in the myocardium was found to be increased during cardiac hypertrophy and heart failure [ 42 , 43 ], while decreased during ischemia–reperfusion cardiac injury [ 44 ]. In the present study, the decreased miR-128-3p level was also detected in the heart tissues of T2DM rats, but its role in DCM has not been explored.…”

Activation of the sirtuin silent information regulator 1 pathway inhibits pathological myocardial remodeling

“…Conversely, treatment with EX527 abolished the beneficial effect of miR-128 downregulation (Zhan et al, 2021). Taurine, a free intracellular β-amino acid, has cardioprotective effects.…”