Cholesterol induced autophagy via IRE1/JNK pathway promotes autophagic cell death in heart tissue

Area of Science:

• Cardiovascular Biology
• Cellular Stress Response
• Molecular Medicine

Background:

• Cardiovascular diseases (CVDs) are a leading global cause of mortality.
• Hypercholesterolemia's impact on heart tissue molecular mechanisms remains incompletely understood.
• Investigating endoplasmic reticulum (ER) stress and cell death in hypercholesterolemia is crucial.

Purpose of the Study:

• To investigate the molecular mechanisms of ER stress and cell death induced by hypercholesterolemia in a rabbit model.
• To explore the potential beneficial effects of α-tocopherol on cholesterol-induced cardiac changes.
• To elucidate the role of the IRE1/JNK pathway in hypercholesterolemia-mediated cardiac pathology.

Main Methods:

• Utilized rabbit models fed a high-cholesterol diet and cultured H9c2 cardiomyocytes treated with cholesterol.
• Employed molecular biology techniques including western blotting, qRT-PCR, immunofluorescence, and flow cytometry.
• Assessed histological modifications via light and electron microscopy; quantified mitochondrial degradation using confocal microscopy.

Main Results:

• High cholesterol induced excessive autophagic activity via the IRE1/JNK pathway in heart tissue and cardiomyocytes.
• Significant indicators of autophagic cell death were observed, including autophagosomes and organelle loss.
• Neither ER-associated degradation (ERAD) nor apoptotic cell death showed significant changes.
• Inhibition of ER stress or JNK, or α-tocopherol supplementation, counteracted cholesterol's effects.

Conclusions:

• Hypercholesterolemia activates the IRE1/JNK pathway, leading to ER stress and subsequent autophagic cell death in cardiac tissue.
• α-tocopherol demonstrates potential as a regulator of autophagic cell death in cardiomyocytes.
• These findings highlight a critical molecular pathway in cholesterol-induced heart damage and suggest a therapeutic avenue.