PIEZO1 Channel-Mediated Mechanotransduction as a Driver of Cardiac Remodelling

Mechanical pressure overload is a central driver of pathological cardiac hypertrophy and fibrosis, yet the mechanism linking mechanical cues to adverse remodelling remains unclear. Fibroblasts are major effector cells of fibrotic remodelling. Still, the precise mechanism by which fibroblasts decode biomechanical cues in settings such as pressure overload has not been fully resolved. This thesis investigates the Ca2+-permeable mechanosensitive ion channel PIEZO1 in cardiac fibroblasts, aiming to determine how PIEZO1-mediated fibroblast mechanotransduction contributes to hypertrophy and fibrosis under pressure overload, and whether pharmacological inhibition of PIEZO1 signalling could offer therapeutic potential. To address these aims, I generated fibroblast-specific Piezo1 conditional knockout mice and performed transverse aortic constriction, echocardiography, invasive hemodynamic assessment, and anatomical measurements to evaluate both structural and functional outcomes. I did immunohistochemistry and cytokine arrays to characterise fibroblast-immune crosstalk. I isolated Piezo1-WT and Piezo1-KO mouse cardiac fibroblasts, then performed mechanical stretch, whole-cell patch-clamp, and LC-MS/MS secretome analyses to define PIEZO1-dependent effects. I conducted a comprehensive investigation of putative Ca2+-dependent proteins that drive PIEZO1 signalling using pharmacological inhibitors. In this thesis, I found fibroblast-specific PIEZO1 ablation significantly attenuated TAC-induced left ventricular and atrial hypertrophy, preserved systolic function, and reduced fibrotic deposition at 14 days post-TAC. I demonstrated that PIEZO1 activation drove fibroblast secretion of CCL2, thereby mediating the recruitment of CCR2+ monocytes and their pro-inflammatory differentiation, which amplified maladaptive remodelling. Mechanistically, I found that PIEZO1 induced calcium-dependent activation of PKCα-ERK and Pyk2-p38 axes, promoted chemokine expression and myofibroblast transition. Pharmacological inhibition of Pyk2 recapitulated the effects of genetic ablation, suppressing hypertrophy, fibrosis, and partially cardiac dysfunction in vivo. These findings identify fibroblast PIEZO1 as a central mechanotransducer that links pressure overload to immune recruitment. PIEZO1 pathways in fibroblasts were established as novel therapeutic targets for hypertensive heart disease and aortic stenosis, expanding treatment strategies beyond current neurohormonal blockade.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2026

Author dc:creator

• Li, Jinyuan

• Piezo1
• Mechanotransduction
• Cardiac fibrosis
• Pressure-overload-induced heart failure

Statement dc:rights

• open access
• CC BY 4.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

en

Identifier

https://doi.org/10.26190/unsworks/32020

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/107031