Cardiac secreted HSP90α exacerbates pressure overload myocardial hypertrophy and heart failure

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Biochemistry

Background:

• Sustained myocardial hypertrophy, or left ventricular hypertrophy (LVH), is a significant risk factor for adverse cardiovascular outcomes.
• Pressure overload conditions, such as hypertension and aortic stenosis (AS), are primary triggers for LVH.

Purpose of the Study:

• To investigate the clinical association between serum heat shock protein 90 alpha (HSP90α) levels and LVH in patients with hypertension or AS.
• To elucidate the underlying molecular mechanisms of HSP90α in pressure overload-induced cardiac hypertrophy using a mouse model.

Main Methods:

• A pressure overload mouse model was established using transverse aortic constriction (TAC).
• Serum and cardiac tissue levels of HSP90α were measured in patients and mice.
• HSP90α knockdown and extracellular HSP90α (eHSP90α) blockade were performed in the mouse model.
• The interaction between eHSP90α, N-cadherin, and the β-catenin/TCF7 signaling pathway was analyzed.

Main Results:

• Patients with hypertension or AS exhibited elevated serum HSP90α levels that positively correlated with LVH.
• HSP90α levels were increased in cardiac tissues of patients with obstructive hypertrophic cardiomyopathy (HCM) and in mice post-TAC.
• TAC induced enhanced cardiac expression and secretion of HSP90α.
• Knockdown or blockade of HSP90α attenuated cardiac hypertrophy and dysfunction by inhibiting the β-catenin/TCF7 signaling pathway.
• eHSP90α was found to interact with N-cadherin, activating β-catenin and subsequently enhancing hypertrophic gene transcription via TCF7.

Conclusions:

• Serum HSP90α levels are a potential clinical biomarker for LVH in pressure overload conditions.
• Extracellular HSP90α plays a critical role in mediating cardiac hypertrophy and dysfunction through the N-cadherin/β-catenin/TCF7 pathway.
• Targeting the HSP90α-initiated signaling pathway presents a promising therapeutic avenue for managing cardiac hypertrophy and heart failure.