Hypercholesterolemia downregulates autophagy in the rat heart

Area of Science:

• Cardiovascular Science
• Cellular Biology
• Metabolic Disorders

Background:

• Ischemic conditioning's cardioprotective efficiency is reduced in hypercholesterolemia.
• Autophagy is essential for cardioprotection, but its modulation by hypercholesterolemia remains unclear.
• The role of the mammalian target of rapamycin (mTOR) pathway in hypercholesterolemia-induced cardiac dysfunction is not well understood.

Purpose of the Study:

• To investigate the effects of isolated hypercholesterolemia on cardiac autophagy.
• To examine the impact of hypercholesterolemia on programmed cell death pathways, including apoptosis and necroptosis.
• To determine if hypercholesterolemia modulates the mTOR pathway in the heart.

Main Methods:

• Male Wistar rats were fed either a normal chow or a cholesterol-enriched diet for 12 weeks.
• Plasma total cholesterol levels were measured to confirm hypercholesterolemia.
• Western blot analysis was used to assess markers of autophagy, mTOR pathway, apoptosis, and necroptosis in cardiac tissue.

Main Results:

• Isolated hypercholesterolemia significantly reduced cardiac autophagy markers (LC3-II, Beclin-1, Rubicon, RAB7).
• The mTOR pathway was activated, indicated by increased ribosomal S6 phosphorylation.
• Apoptosis markers (cleaved caspase-3) were elevated, while necroptosis markers (RIP1, RIP3, MLKL) showed no significant difference.

Conclusions:

• Isolated hypercholesterolemia suppresses basal cardiac autophagy, potentially due to mTOR pathway activation.
• Reduced autophagy and increased apoptosis in hypercholesterolemic hearts may underlie diminished cardioprotection.
• Cardiac necroptosis is not affected by isolated hypercholesterolemia.