Mechanical Stretching Simulates Cardiac Physiology and Pathology through Mechanosensor Piezo1

Abstract

The dynamics of a living body enables organs to experience mechanical stimulation at cellular level. The human cardiomyocytes cell line provides a source for simulating heart dynamics; however, a limited understanding of the mechanical stimulation effect on them has restricted potential applications. Here, we investigated the effect of mechanical stimulation on the cardiac function-associated protein expressions in human cardiomyocytes. Human cardiomyocyte cell line AC16 was subjected to different stresses: 5% mild and 25% aggressive, at 1 Hz for 24 h. The stretched cardiomyocytes showed down-regulated Piezo1, phosphorylated-Ak transforming serine473 (P-AKTS473), and phosphorylated-glycogen synthase kinase-3 beta serine9 P-GSK3βS9 compared to no stretch. In addition, the stretched cardiomyocytes showed increased low-density lipoprotein receptor-related protein 6 (LRP6), and phosphorylated-c-Jun N-terminal kinase threonine183/tyrosine185 (P-JNKT183/Y185). When Piezo inhibitor was added to the cells, the LRP6, and P-JNKT183/Y185 were further increased under 25%, but not 5%, suggesting that higher mechanical stress further activated the wingless integrated-(Wnt)-related signaling pathway when Piezo1 was inhibited. Supporting this idea, when Piezo1 was inhibited, the expression of phosphorylated-endothelial nitric oxide synthase serine1177 (P-eNOSS1177) and release of calcium ions were reduced under 25% compared to 5%. These studies demonstrate that cyclic mechanical stimulation affects cardiac function-associated protein expressions, and Piezo1 plays a role in the protein regulation.

When Stiffness Matters: Mechanosensing in Heart Development and Disease

“…Another, and probably the most known, stretch sensor in CMs involves the cytoskeleton and allows the process of mechanotransduction to occur at a different site from where the strain is applied (Ingber, 2003a,b). These models are supported by in vitro studies where it has been shown that the application of a mechanical stimulus to isolated CMs or stem cells results in changes in gene and protein expression that are indicative of a (patho)physiological response or cell maturation and differentiation (Vining and Mooney, 2017;Kim et al, 2018;Wong et al, 2018). A possible mechanism for this involves many different proteins ranging from the ECM molecules to membrane and intracellular proteins that bind to the cytoskeleton and orchestrate the cellular response to different microenvironments.…”

“…However, it is likely that the same mechanosensing pathways described previously allow also the maturation of the different cultured 3D tissues. Recently, it has been shown that following mechanical stretch, Piezo1, phosphorylated-Ak transforming serine473 (P-AKTS473), and phosphorylated-glycogen synthase kinase-3 beta serine9 (P-GSK3) expression was downregulated in the human CM cell line AC16 (Wong et al, 2018). In another study, the mechanical stretch induces endothelial nitric oxide synthase gene expression in neonatal rat CMs (Cheng et al, 2009).…”

Hypoxia modulates protein phosphatase 2A through HIF‐1α dependent and independent mechanisms in human aortic smooth muscle cells and ventricular cardiomyocytes

“…• Demonstrates that hypoxia modulates the PP2A system What is the clinical significance (Davidson et al, 2005), and have been used as a cardiomyocyte model to study the effect of mechanical stretch and hypoxia (Lee et al, 2018;Wong et al, 2018).…”

Closer to Nature Through Dynamic Culture Systems

“…Piezo1 is required for maintaining arterial wall thickness, as well as calcium and transglutaminase activity in arterial smooth muscle cells of mice [21]. It has also been reported that Piezo1 modulates calcium ion levels in human cardiomyocytes [22]; however, the mechanisms involving Piezo1 and Piezo2 mechanotransduction in mammals remain unknown.…”