Aránguiz P, Romero P, Vásquez F, Flores-Vergara R, Aravena D, Sánchez G, González M, Olmedo I, Pedrozo Z
Escuela de Química y Farmacia, Facultad de Medicina, Universidad Andrés Bello, Viña del Mar, Chile.
Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago de Chile, Chile; Advanced Center for Chronic Diseases, Facultad de Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago de Chile, Chile.
Biochim Biophys Acta Mol Basis Dis. 2021 Jan 1;1867(1):165986. doi: 10.1016/j.bbadis.2020.165986. Epub 2020 Oct 13.
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. Polycystin-1 (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）过程中，心肌细胞激活调节细胞存活和死亡的信号通路，并释放调节成纤维细胞向肌成纤维细胞分化的因子。这些效应背后的机制尚未完全明确。多囊蛋白-1（PC1）是一种对心脏功能至关重要的机械感受器。本研究旨在评估PC1在心肌细胞存活中的作用、其在心肌细胞中促纤维化因子表达的作用，以及其对I/R诱导的心脏成纤维细胞功能的旁分泌效应。分别在野生型和PC1基因敲除（PC1 KO）小鼠以及PC1基因敲低（siPC1）的新生大鼠心室肌细胞（NRVM）中诱导体内和体外I/R以及模拟体外I/R（sI/R）。用再灌注后NRVM或siPC1-NRVM上清液衍生的条件培养基（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。接受体内和体外I/R的PC1-KO小鼠梗死面积更大，sI/R后siPC1-NRVM的坏死率高于对照组。sI/R期间PC1激活了促存活的AKT蛋白，并诱导了PC1-AKT信号通路依赖性的结缔组织生长因子（CTGF）表达。此外，sI/R-NRVM的条件培养基诱导NRCF中PC1依赖性的成纤维细胞向肌成纤维细胞分化。这一新证据表明，PC1可能通过激活AKT减轻I/R期间的心脏损伤，并通过AKT调节心肌细胞中CTGF的表达。此外，PC1-NRVM在sI/R期间调节成纤维细胞向肌成纤维细胞的分化。因此，PC1可能成为I/R损伤诱导的心脏重塑的新关键调节因子。
