Yang Jing-Jing, Zhang Nan, Zhou Zi-Ying, Ni Jian, Feng Hong, Li Wen-Jing, Mou Shan-Qi, Wu Hai-Ming, Deng Wei, Liao Hai-Han, Tang Qi-Zhu
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China.
Front Cell Dev Biol. 2021 Oct 18;9:688238. doi: 10.3389/fcell.2021.688238. eCollection 2021.
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 . Phenylephrine (PE)-treated neonatal rat cardiomyocytes (NRCMs) were used for further investigation . 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 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.
本研究旨在探讨受体相互作用蛋白激酶2（RIP2）在压力超负荷诱导的心脏重塑中的作用及机制。收集人类衰竭或健康供体心脏以检测RIP2表达。对RIP2心肌细胞特异性过表达、RIP2全身敲除或野生型小鼠进行假手术或主动脉缩窄（AB）手术，以建立压力超负荷诱导的心脏重塑模型。用去甲肾上腺素（PE）处理新生大鼠心肌细胞（NRCMs）以进行进一步研究。RIP2在人类衰竭心脏、小鼠重塑心脏和Ang II处理的NRCMs中的表达显著上调。RIP2过表达明显加重压力超负荷诱导的心脏重塑。机制上，RIP2过表达显著增加TAK1、P38和JNK1/2的磷酸化，并增强IκBα/p65信号通路。用特异性抑制剂抑制TAK1活性可完全阻止RIP2过表达诱导的心脏重塑。本研究进一步证实，NRCM中RIP2过表达可加剧PE诱导的NRCM肥大，而通过特异性siRNA使TAK1沉默可完全挽救RIP2过表达介导的心肌细胞肥大。此外，本研究表明RIP2可在HEK293细胞中与TAK1结合，且PE可促进它们在NRCM中的相互作用。令人惊讶的是，我们发现RIP2过表达在12和18月龄时导致自发性心脏重塑，这证实了RIP2过表达的严重恶化作用。最后，我们表明RIP2全身敲除减轻了压力超负荷诱导的心脏重塑，同时降低了TAK1/JNK1/2/P38和IκBα/p65信号通路。综上所述，RIP2介导的TAK1/P38/JNK1/2和IκBα/p65信号通路激活在压力超负荷诱导的心脏重塑以及RIP2过表达诱导的自发性心脏重塑中起关键作用，抑制RIP2可能是预防心脏重塑的潜在策略。
