Abstract
BackgroundHypertension affects approximately 1.3 billion adults aged 30-79 years worldwide. Hypertension-induced arterial fibrotic remodelling, including the coronary arteries, contributes to hypertension-induced organ damage. Hypertension promotes extracellular matrix accumulation in the perivascular area, reducing coronary artery compliance and restricting blood flow. Wnt/β-catenin signalling and its downstream protein WISP-1 are implicated in fibrotic remodelling. This study aimed to investigate the involvement of Wnt/β-catenin signalling pathway and WISP-1 in hypertension-induced coronary artery fibrotic remodelling.
Methods
ApoE-/- mice were subcutaneously infused with 500ng/kg/min angiotensin II (Ang II) using osmotic micro-pumps for 28 days with oral administration of ETC-159 (in DMSO: n=18), a Porcupine inhibitor, to inhibit Wnt secretion, or equal amount of DMSO (vehicle control: n=18). ApoE-/- mice without Ang II were normotensive controls. Cultured human cardiac fibroblasts (HCFs) were treated with recombinant human WISP-1 protein (500ng/ml) and the effects of WISP-1 protein on collagen processing, activation, and proliferation were evaluated.
Results
Ang II significantly increased blood pressure, plasma Wnt3a levels and cardiac hypertrophic remodelling (increased heart weight to tibia length ratio). Ang II did not alter collagen content in the coronary artery perivascular area. ETC-159 suppressed the increase in plasma Wnt3a protein and hindered systolic blood pressure elevation, and attenuated hypertension-induced cardiac hypertrophic remodelling, but increased LDL/VLDL cholesterol level. The in vitro analyses in HCFs illustrated WISP-1 protein activated Akt signalling, thereby, promoting collagen processing. WISP-1 protein induced zinc-mediated metalloproteinase-dependent cleavage of type I procollagen N-terminal propeptide from type I procollagen, accelerating tropocollagen formation. Additionally, WISP-1 protein promoted phenotypic switch of quiescent fibroblasts to α-SMA-positive myofibroblasts.
Conclusion
In conclusion, the Wnt/β-catenin signalling pathway and its downstream WISP-1 are involved in hypertensive cardiac remodelling. Furthermore, WISP-1 is a pivotal mediator of collagen processing and fibroblast activation. This study indicates that targeting WISP-1 is a promising therapeutic strategy for attenuating cardiac fibrotic disease.
Date of Award | 21 Mar 2023 |
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Original language | English |
Awarding Institution |
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Supervisor | Sarah J George (Supervisor) & Jason L Johnson (Supervisor) |