Cardiomyocyte-Specific RIP2 Overexpression Exacerbated Pathologic Remodeling and Contributed to Spontaneous Cardiac Hypertrophy

Abstract

This study aimed to investigate the role and mechanisms of Receptor interacting protein kinase 2 (RIP2) in pressure overload-induced cardiac remodeling. Human failing or healthy donor hearts were collected for detecting RIP2 expression. RIP2 cardiomyocyte-specific overexpression, RIP2 global knockout, or wild-type mice were subjected to sham or aortic banding (AB) surgery to establish pressure overload-induced cardiac remodeling in vivo. Phenylephrine (PE)-treated neonatal rat cardiomyocytes (NRCMs) were used for further investigation in vitro. The expression of RIP2 was significantly upregulated in failing human heart, mouse remodeling heart, and Ang II-treated NRCMs. RIP2 overexpression obviously aggravated pressure overload-induced cardiac remodeling. Mechanistically, RIP2 overexpression significantly increased the phosphorylation of TAK1, P38, and JNK1/2 and enhanced IκBα/p65 signaling pathway. Inhibiting TAK1 activity by specific inhibitor completely prevented cardiac remodeling induced by RIP2 overexpression. This study further confirmed that RIP2 overexpression in NRCM could exacerbate PE-induced NRCM hypertrophy and TAK1 silence by specific siRNA could completely rescue RIP2 overexpression-mediated cardiomyocyte hypertrophy. Moreover, this study showed that RIP2 could bind to TAK1 in HEK293 cells, and PE could promote their interaction in NRCM. Surprisingly, we found that RIP2 overexpression caused spontaneous cardiac remodeling at the age of 12 and 18 months, which confirmed the powerful deterioration of RIP2 overexpression. Finally, we indicated that RIP2 global knockout attenuated pressure overload-induced cardiac remodeling via reducing TAK1/JNK1/2/P38 and IκBα/p65 signaling pathways. Taken together, RIP2-mediated activation of TAK1/P38/JNK1/2 and IκBα/p65 signaling pathways played a pivotal role in pressure overload-induced cardiac remodeling and spontaneous cardiac remodeling induced by RIP2 overexpression, and RIP2 inhibition might be a potential strategy for preventing cardiac remodeling.

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“…RIP2 overexpression aggravates myocardial infarction-related cardiac remodeling, and its mechanism is related to the activation of p38 phosphorylation (19). Previously (60), it was demonstrated that the expression of RIP2 was significantly increased in cardiac cells in patients with heart failure, mice with aortic banding surgery-induced pressure overload and phenylephrine-treated cardiomyocytes in vitro. Notably, RIP2 overexpression aggravates pressure overload-induced cardiac remodeling (60).…”

“…Previously (60), it was demonstrated that the expression of RIP2 was significantly increased in cardiac cells in patients with heart failure, mice with aortic banding surgery-induced pressure overload and phenylephrine-treated cardiomyocytes in vitro. Notably, RIP2 overexpression aggravates pressure overload-induced cardiac remodeling (60). The expression and function of RIP2 in CKD-associated cardiac injury have not yet been confirmed.…”

Cryptotanshinone Attenuated Pathological Cardiac Remodeling In Vivo and In Vitro Experiments

“…After 90 min of differential attachment culture, the CFs were attached to the bottom of culture dish while the NRCMs existed in the culture medium. The NRCMs were counted and cultured in a 6-well plate with cell density of 5 × 10 6 and treated with AngII (1 μM) or PBS in the presence of different concentrations of CTS (0, 3, 6, and 12 μM) for 12 h. The CFs were passaged to the second generation and then were counted and cultured in a 6-well plate with a cell density of 2 × 10 6 and treated with TGF-β (10 μM) or PBS in the presence of different concentrations of CTS (0, 3, 6, and 12 μM) for 12 h. The dose of AngII (1 μM) and TGF-β(10 μM) was performed as previously described [20,21]. Western blot was performed to assess the effect of CTS.…”