PCSK9 Inhibition Regulates Infarction-Induced Cardiac Myofibroblast Transdifferentiation via Notch1 Signaling

by Selleckchem | Jul 09 2023

Increasing evidence suggests that PCSK9 inhibition protects cardiomyocytes against ischemia-reperfusion injury after myocardial infarction. However, it is not clear whether PCSK9 inhibitor (PCSK9i) affects cardiac fibroblasts (CFs) activation after MI. In this study we used SBC-115076, an antagonist of PCSK9, to investigate the role of PCSK9i in the conversion of CFs to cardiac myofibroblasts (CMFs) after MI and provided a basic for its clinical application in cardiac fibrosis after MI. In vivo study, PCSK9i was injected into mice 4 days after MI. Cardiac function and degree of fibrosis were evaluated by echocardiographic and tissue staining after treatment. Western blot showed that PCSK9i treatment decreases expression of α-SMA, collagen and increases expression of Notch1 in border infarct area. Vitro studies showed that PCSK9i decreased the degree of fibrosis, migration, and collagen fiber deposition in CFs. Confocal microscopy imaging also showed that hypoxia contributes to the formation of α-SMA stress filaments, and PCSK9i alleviated this state. Moreover, overexpression of Notch1 further suppress the activation of CFs under hypoxia. These results revealed that SBC-115076 ameliorates cardiac fibrosis and ventricular dysfunction post-myocardial infarction through inhibition of the differentiation of cardiac fibroblasts to myofibroblasts via Notch1/Hes1 signaling.

Comments:

The study you mentioned investigated the effects of PCSK9 inhibition using SBC-115076, a PCSK9 antagonist, on cardiac fibroblast activation after myocardial infarction (MI). The researchers aimed to determine whether PCSK9 inhibition could prevent the conversion of cardiac fibroblasts (CFs) to cardiac myofibroblasts (CMFs) after MI, and thereby potentially reduce cardiac fibrosis.

In the in vivo part of the study, mice were injected with PCSK9 inhibitor (PCSK9i) four days after experiencing MI. The researchers evaluated cardiac function and the extent of fibrosis through echocardiographic imaging and tissue staining after treatment. Western blot analysis was performed to measure the expression levels of α-SMA (alpha-smooth muscle actin), collagen, and Notch1 in the border infarct area. The results showed that PCSK9i treatment reduced the expression of α-SMA and collagen while increasing the expression of Notch1 in the border infarct area.

In the in vitro studies, CFs were treated with PCSK9i to investigate its effects on fibrosis-related processes such as migration and collagen fiber deposition. The degree of fibrosis, migration, and collagen fiber deposition were all decreased in CFs treated with PCSK9i. Confocal microscopy imaging revealed that hypoxia contributed to the formation of α-SMA stress filaments in CFs, but PCSK9i alleviated this state.

Furthermore, the researchers explored the involvement of the Notch1/Hes1 signaling pathway in the effects of PCSK9i on CF activation under hypoxic conditions. Overexpression of Notch1 further suppressed CF activation under hypoxia, suggesting that PCSK9i may exert its effects on CFs through modulation of the Notch1/Hes1 signaling pathway.

Overall, the findings of this study suggest that SBC-115076, a PCSK9 inhibitor, can ameliorate cardiac fibrosis and improve ventricular dysfunction following myocardial infarction. These effects are likely mediated through the inhibition of CF-to-CMF differentiation via the Notch1/Hes1 signaling pathway. These results provide a basis for considering the clinical application of PCSK9 inhibitors in the context of cardiac fibrosis following MI.