Translational Medicine Center, Baotou Central Hospital, Baotou, China.
Department of Cardiology, Baotou Central Hospital, Baotou, China.
J Cell Biochem. 2019 Mar;120(3):3071-3081. doi: 10.1002/jcb.27479. Epub 2018 Nov 28.
The soluble form of guanylyl cyclase (sGC) is the main receptor for the signaling agent nitric oxide (NO), which regulates cardiomyocyte contractile function and attenuates cardiomyocyte hypertrophy. sGC catalyzes the formation of cyclic guanosine monophosphate (cGMP), a regulator of vascular tone, and cardiac NO-sGC-cGMP signaling modulates cardiac stress responses, including ischemia and reperfusion (IR) injury. Here, we investigated the role of GUCY1B3 (the β subunit of sGC) in cardiomyocyte IR injury and myocardial infarction (MI) in vitro and in vivo. GUCY1B3 was upregulated in neonatal rat ventricular myocytes in response to IR injury, and GUCY1B3 overexpression restored IR-induced cell death and apoptosis. Treatment with specific inhibitors of PKCδ, PKCε, and Akt suggested that the protective effects of GUCY1B3 were mediated by PKCε/Akt signaling. In a mouse model of coronary artery ligation-induced MI, GUCY1B3 silencing aggravated MI-induced cardiac dysfunction and increased infarct size and exacerbated cardiomyocyte apoptosis in association with the inactivation of PKCε and Akt. Our results suggest that GUCY1B3 exerts cardioprotective effects through the modulation of the PKCε/Akt activity and identify a potential mechanism involved in NO-sGC-cGMP signaling in the heart.
可溶性鸟苷酸环化酶（sGC）的形式是信号转导剂一氧化氮（NO）的主要受体，它调节心肌细胞的收缩功能并减弱心肌细胞肥大。sGC 催化环鸟苷酸（cGMP）的形成，cGMP 是血管张力的调节剂，心脏的 NO-sGC-cGMP 信号转导调节心脏的应激反应，包括缺血再灌注（IR）损伤。在这里，我们研究了 GUCY1B3（sGC 的β亚基）在体外和体内心肌细胞 IR 损伤和心肌梗死（MI）中的作用。GUCY1B3 在响应 IR 损伤时在新生大鼠心室肌细胞中上调，并且 GUCY1B3 的过表达恢复了 IR 诱导的细胞死亡和细胞凋亡。PKCδ、PKCε 和 Akt 的特异性抑制剂的处理表明 GUCY1B3 的保护作用是通过 PKCε/Akt 信号转导介导的。在冠状动脉结扎诱导的 MI 小鼠模型中，GUCY1B3 沉默加重了 MI 诱导的心脏功能障碍，并增加了梗塞面积，并与 PKCε 和 Akt 的失活相关联，加重了心肌细胞凋亡。我们的结果表明，GUCY1B3 通过调节 PKCε/Akt 活性发挥心脏保护作用，并确定了心脏中涉及 NO-sGC-cGMP 信号转导的潜在机制。
