LncRNA-H19 Drives Cardiomyocyte Senescence by Targeting miR-19a/socs1/p53 Axis

Abstract

Purpose: Cardiomyocyte senescence is associated with a progressive decline in cardiac physiological function and the risk of cardiovascular events. lncRNA H19 (H19), a well-known long noncoding RNA (lncRNA), is involved in the pathophysiological process of multiple cardiovascular disease such as heart failure, cardiac ischemia and fibrosis. However, the role of H19 in cardiomyocyte senescence remains to be further explored.Methods: Senescence-associated β-galactosidases (SA-β-gal) staining was used to detect cardiomyocyte senescence. Western blot, qRT-PCR and luciferase reporter assay were employed to evaluate the role of H19 in cardiomyocyte senescence and its underling molecular mechanism.Results: H19 level was significantly increased in high glucose-induced senescence cardiomyocytes and aged mouse hearts. Overexpression of H19 enhanced the number of SA-β-gal-positive cells, and the expression of senescence-related proteins p53 and p21, whereas H19 knockdown exerted the opposite effects. Mechanistically, H19 was demonstrated as a competing endogenous RNA (ceRNA) for microRNA-19a (miR-19a): H19 overexpression downregulated miR-19a level, while H19 knockdown upregulated miR-19a. The expression of SOSC1 was dramatically increased in senescence cardiomyocytes and aged mouse hearts. Further experiments identified SOCS1 as a downstream target of miR-19a. H19 upregulated SOCS1 expression and activated the p53/p21 pathway by targeting miR-19a, thus promoting the cardiomyocytes senescence.Conclusion: Our results show that H19 is a pro-senescence lncRNA in cardiomyocytes acting as a ceRNA to target the miR-19a/SOCS1/p53/p21 pathway. Our research reveals a molecular mechanism of cardiomyocyte senescence regulation and provides a novel target of the therapy for senescence-associated cardiac diseases.

ARID1A knockdown enhances carcinogenesis features and aggressiveness of Caco-2 colon cancer cells: An in vitro cellular mechanism study

“…Normally, the somatic cells has a limited lifespan - they can be replicated (but limitedly) and finally undergo cellular senescence, which is the process of permanent cell cycle arrest. Cellular senescence is a cell protective mechanism that can be detected by measuring the SA-β-gal activity 52 , 53 . Several lines of evidence have reported that suppression of cellular senescence is associated with the enhanced carcinogenesis 54 , 55 .…”

Decreased miR-17-92 Cluster Correlates With the Senescent Features and Disrupted Oxidative Homeostasis, and the Impaired Therapeutic Efficacy of Adipose Tissue-derived Mesenchymal Stem Cells

“…In addition to the regulation of p21 expression in cellular senescence, miR-17-92 cluster has been known to affect senescence by regulating several other genes, such as Smurf1 and SOSC1 [23,24]. Recently, disrupted oxidative homeostasis and high ROS level have been characterized in MSC senescence.…”

MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Redox Control of Cell Senescence

“…The authors demonstrated that H19 is causally implicated in the effects of H 2 O 2 and that the increased H19 by sequestering miR-22, a direct inhibitor of the lymphoid enhancing factor-1 (LEF1), could activate the downstream Wnt/β-catenin signaling contributing to degenerative events [264]. Similarly, the high H19 has been recently implicated in cardiomyocyte senescence functioning as a ceRNA for miR-19a [265]. In this work, Zhuang et al demonstrate that the increase of H19, by scavenging miR-19a, consequently upregulated the suppressor of cytokine signaling 1 (SOCS1) expression (a target of this miRNA), thus enhancing the p53/p21 pathway [265].…”