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.
Highlights
Cardiomyocyte senescence is associated with abnormalities of cardiac performance and structure with declination of cardiac relaxation and contraction, increase in left ventricle weight and cardiomyocyte size, as well as excess interstitial extracellular matrix deposition
Our data show that H19 acts as competing endogenous RNA of miR-19a to promote suppressor of cytokine signaling 1 (SOCS1) expression in cardiac senescence by stimulation of p53 and p21
The expression of H19 was significantly increased in these senescent Neonatal mouse ventricular cells (NMVCs) (Figure 1C)
Summary
Cardiomyocyte senescence is associated with abnormalities of cardiac performance and structure with declination of cardiac relaxation and contraction, increase in left ventricle weight and cardiomyocyte size, as well as excess interstitial extracellular matrix deposition. Cardiomyocyte senescence is a physiological process during the natural aging heart and creates a lower threshold for many cardiac diseases to occur such as heart failure (Shah et al, 2015). It is considered that oxygen free radical damage, telomere shortening and gene mutation are the main causes of senescence (Yuan et al, 2019; Oliveira de Almeida et al, 2020). P53-p21 and p16INK4A-Rb have been recognized as the main molecular pathways for cell senescence (Rufini et al, 2013). Senescence is a complicated process involving a number of factors/pathways. Deciphering the molecular mechanisms of cardiomyocyte senescence will be helpful to improve our understanding of agingassociated cardiac diseases and to find novel approaches for treatment
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