Yes-Associated Protein (Yap) Is Up-Regulated in Heart Failure and Promotes Cardiac Fibroblast Proliferation

Area of Science:

• Cardiovascular Biology
• Molecular Signaling
• Fibrosis Research

Background:

• Left ventricular (LV) heart failure (HF) is a leading cause of mortality, characterized by myocardial remodeling and fibrosis.
• The role of transcriptional co-activator Yes-associated protein (Yap) in human LV HF remains unclear.
• Yap is a key downstream effector of the HIPPO signaling pathway and is crucial for cardiomyocyte survival.

Purpose of the Study:

• To investigate the role and status of Yap in human LV heart failure.
• To determine the impact of profibrotic stimuli on Yap signaling in cardiac fibroblasts.
• To elucidate the contribution of Yap to cardiac fibroblast proliferation and LV remodeling.

Main Methods:

• Analysis of Yap levels in LV tissue from HF patients.
• In vitro studies using human ventricular cardiac fibroblasts subjected to TGFβ and hypoxia.
• Assessment of Yap, LATS1, CTGF, Akt, ERK1/2, and mTOR pathway components.
• Yap depletion experiments to evaluate its role in fibroblast proliferation and signaling.

Main Results:

• Yap is elevated in human LV HF tissue, correlating with decreased LATS1 activation and increased CTGF.
• TGFβ/hypoxia treatment of cardiac fibroblasts increases Yap, reduces LATS1 activation, and promotes proliferation and collagen I production.
• Yap depletion inhibits TGFβ/hypoxia-induced fibroblast proliferation and Akt phosphorylation.
• TGFβ/hypoxia also enhances Akt and ERK1/2 phosphorylation in fibroblasts, mirroring observations in HF patient tissues.

Conclusions:

• Yap is upregulated in human LV heart failure and promotes cardiac fibroblast proliferation.
• Yap signaling contributes to profibrotic responses and may play a significant role in LV remodeling.
• Yap emerges as a potential mediator in the pathogenesis of human HF, warranting further investigation.