HTRA1-driven detachment of type I collagen from endoplasmic reticulum contributes to myocardial fibrosis in dilated...

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Fibrosis Research

Background:

• Dilated cardiomyopathy (DCM) pathogenesis involves aberrant type I collagen (Col1) secretion and deposition, leading to myocardial fibrosis.
• The exact molecular mechanisms driving Col1 synthesis and secretion in DCM remain incompletely understood.

Purpose of the Study:

• To investigate the role of HtrA serine peptidase 1 (HTRA1) in the pathogenesis of myocardial fibrosis in DCM.
• To elucidate the molecular mechanisms by which HTRA1 influences Col1 secretion and to explore its therapeutic potential.

Main Methods:

• RNA-sequencing, immunoblotting, qRT-PCR, immunohistochemistry, and immunofluorescence were used to assess HTRA1 expression in human and mouse DCM tissues.
• Pearson's correlation analysis examined the relationship between HTRA1 levels and fibrosis indicators (ECV, native T1, LGE).
• In vitro studies assessed the impact of HTRA1 suppression on cardiac fibroblasts and Col1 secretion, investigating its role in ER exit site formation.
• In vivo studies utilized AAV9-shHTRA1-GFP to evaluate the effects of HTRA1 knockdown on myocardial fibrosis and cardiac function in a mouse model of DCM.

Main Results:

• HTRA1 expression was significantly increased in DCM patients and correlated positively with myocardial fibrosis indicators.
• HTRA1 suppression inhibited cardiac fibroblast to myofibroblast conversion and reduced Col1 secretion by promoting ER exit site formation.
• HTRA1 knockdown led to ER stress, ER autophagy induction, and impaired Col1 secretion.
• In vivo HTRA1 knockdown suppressed myocardial fibrosis and improved left ventricular function in DCM mice.

Conclusions:

• HTRA1 plays a crucial role in promoting Col1 secretion and myocardial fibrosis in DCM.
• Targeting HTRA1-mediated collagen secretion presents a promising therapeutic strategy for DCM-associated myocardial fibrosis.