During ischemia/reperfusion (I/R), cardiomyocytes activate pathways that regulate cell survival and death and release factors that modulate fibroblast-to-myofibroblast differentiation. The mechanisms underlying these effects are not fully understood. Polycystin­1 (PC1) is a mechanosensor crucial for cardiac function. This work aims to assess the role of PC1 in cardiomyocyte survival, its role in profibrotic factor expression in cardiomyocytes, and its paracrine effects on I/R-induced cardiac fibroblast function.

In vivo and ex vivo I/R and simulated in vitro I/R (sI/R) were induced in wild-type and PC1-knockout (PC1 KO) mice and PC1-knockdown (siPC1) neonatal rat ventricular myocytes (NRVM), respectively. Neonatal rat cardiac fibroblasts (NRCF) were stimulated with conditioned medium (CM) derived from NRVM or siPC1-NRVM supernatant after reperfusion and fibroblast-to-myofibroblast differentiation evaluated. Infarcts were larger in PC1-KO mice subjected to in vivo and ex vivo I/R, and necrosis rates were higher in siPC1-NRVM than control after sI/R. PC1 activated the pro-survival AKT protein during sI/R and induced PC1-AKT-pathway-dependent CTGF expression. Furthermore, conditioned media from sI/R-NRVM induced PC1-dependent fibroblast-to-myofibroblast differentiation in NRCF.

This novel evidence shows that PC1 mitigates cardiac damage during I/R, likely through AKT activation, and regulates CTGF expression in cardiomyocytes via AKT. Moreover, PC1-NRVM regulates fibroblast-to-myofibroblast differentiation during sI/R. PC1, therefore, may emerge as a new key regulator of I/R injury-induced cardiac remodeling.

在缺血/再灌注（I / R）期间，心肌细胞激活调节细胞存活和死亡的途径，并释放调节成纤维细胞向成肌纤维细胞分化的因子。这些作用的潜在机制尚不完全清楚。Polycystin1（PC1）是对心脏功能至关重要的机械传感器。这项工作旨在评估PC1在心肌细胞存活中的作用，其在心肌细胞中纤维化因子表达中的作用以及其旁分泌对I / R诱导的心脏成纤维细胞功能的影响。

在野生型和PC1-敲除（PC1 KO）小鼠和PC1-敲除（siPC1）新生大鼠心室肌细胞（NRVM）中诱导了体内和离体I / R和模拟的体外I / R（sI / R），分别。再灌注后，用源自NRVM或siPC1-NRVM上清液的条件培养基（CM）刺激新生大鼠心脏成纤维细胞（NRCF），并评估成纤维细胞向肌成纤维细胞的分化。在体内和离体的PC1-KO小鼠中梗死面积更大sI / R后，siPC1-NRVM中的I / R和坏死率高于对照。PC1在sI / R过程中激活了生存前的AKT蛋白，并诱导PC1-AKT途径依赖性CTGF表达。此外，来自sI / R-NRVM的条件培养基在NRCF中诱导PC1依赖性成纤维细胞向成肌纤维细胞的分化。

这种新颖的证据表明，I / R，可能通过AKT激活期间PC1减轻心肌损伤，并且调节心肌CTGF表达通过AKT。此外，PC1-NRVM在sI / R期间调节成纤维细胞向成肌纤维细胞的分化。因此，PC1可能会成为I / R损伤引起的心脏重塑的新关键调节因子。