Cardiac Fibrosis in Proteotoxic Cardiac Disease is Dependent Upon Myofibroblast TGF‐β Signaling

Abstract

Background Transforming growth factor beta ( TGF ‐β) is an important cytokine in mediating the cardiac fibrosis that often accompanies pathogenic cardiac remodeling. Cardiomyocyte‐specific expression of a mutant αB‐crystallin (Cry AB R 120G ), which causes human desmin‐related cardiomyopathy, results in significant cardiac fibrosis. During onset of fibrosis, fibroblasts are activated to the so‐called myofibroblast state and TGF ‐β binding mediates an essential signaling pathway underlying this process. Here, we test the hypothesis that fibroblast‐based TGF ‐β signaling can result in significant cardiac fibrosis in a disease model of cardiac proteotoxicity that has an exclusive cardiomyocyte‐based etiology. Methods and Results Against the background of cardiomyocyte‐restricted expression of Cry AB R 120G , we have partially ablated TGF ‐β signaling in cardiac myofibroblasts to observe whether cardiac fibrosis is reduced despite the ongoing pathogenic stimulus of Cry AB R 120G production. Transgenic Cry AB R 120G mice were crossed with mice containing a floxed allele of TGF ‐β receptor 2 ( Tgfbr2 f/f ). The double transgenic animals were subsequently crossed to another transgenic line in which Cre expression was driven from the periostin locus ( Postn ) so that Tgfbr2 would be ablated with myofibroblast conversion. Structural and functional assays were then used to determine whether general fibrosis was affected and cardiac function rescued in Cry AB R 120G mice lacking Tgfbr2 in the myofibroblasts. Ablation of myofibroblast specific TGF ‐β signaling led to decreased morbidity in a proteotoxic disease resulting from cardiomyocyte autonomous expression of Cry AB R 120G . Cardiac fibrosis was decreased and hypertrophy was also significantly attenuated, with a significant improvement in survival probability over time, even though the primary proteotoxic insult continued. Conclusions Myofibroblast‐targeted knockdown of Tgfbr2 signaling resulted in reduced fibrosis and improved cardiac function, leading to improved probability of survival.

Circulating extra-cellular RNAs, myocardial remodeling, and heart failure in patients with acute coronary syndrome

“…The top five GO categories are a proteinaceous extracellular matrix (GO:0005578), biological adhesion (GO:0022610), enzyme binding (GO:0031012), regulation of transcription from RNA polymerase promoter (GO:0006357), and tissue development (GO:0009888). Notably, there is a recurring theme of the GO term enrichment in extracellular matrix remodeling and cell differentiation, both of which has been shown to be regulated by TFG-β [47,48]. Together, our data support that miR-29c-3p, miR-584-5p, and miR-1247-5p affect cardiac remodeling structurally by influencing cell death and fibrosis, in part through the p53 and TFG-β signaling pathways.…”

Rutaecarpine prevents hypertensive cardiac hypertrophy involving the inhibition of Nox4‐ROS‐ADAM17 pathway

“…RNA extraction and quantitative real‐time PCR were performed as described previously . Real‐time PCR used primers for atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), Col I, Col III, Nox4, ADAM17, TNF‐α and the gene‐specific for GADPH was chose as an inner control.…”

Cardiosomal microRNAs Are Essential in Post-Infarction Myofibroblast Phenoconversion

“…Mounting evidence has reinforced the concept that cardiac fibroblasts are much more than simple homeostatic regulators of the extracellular matrix (ECM) turnover, being in fact integrally involved in all aspects of the repair and remodeling of the heart occurring after an ischemic injury [1][2][3][4]. Although cardiac fibroblasts have been less widely studied than cardiomyocytes, it is becoming increasingly apparent that these cells (and their differentiated phenotype, myofibroblasts) are integral to the development, normal function, and repair of the heart, and are the dominating cell type in the processes of cardiac remodeling and fibrosis [4][5][6][7].…”