Hypercholesterolemia inhibits L-type calcium current in coronary macro-, not microcirculation

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Atherosclerosis Research

Background:

• Hypercholesterolemia (HC) is a significant risk factor for coronary heart disease (CHD).
• Coronary ion regulation, particularly calcium, is implicated in CHD development.
• The impact of high-fat, high-cholesterol diets on coronary arterial smooth muscle (CASM) ion channels remains unclear.

Purpose of the Study:

• To investigate the effect of diet-induced HC on CASM voltage-gated calcium current (I(Ca)).
• To determine if HC affects calcium channel activity in different sizes of coronary arteries.

Main Methods:

• Miniature swine were fed a high-fat, high-cholesterol diet for 20-24 weeks to induce HC.
• CASM were isolated from various coronary artery segments (right coronary artery, small arteries, arterioles).
• Whole-cell voltage clamp electrophysiology was used to measure I(Ca).

Main Results:

• Diet-induced HC significantly reduced L-type I(Ca) by approximately 30% in large coronary arteries (right coronary artery).
• I(Ca) in the coronary microcirculation (small arteries and arterioles) was not affected by HC.
• Neither voltage-dependent activation nor Ca(v)1.2 mRNA/protein levels were altered by HC.
• Inhibition of I(Ca) was reversible with a cholesterol scavenger and mimicked by cholesterol addition.

Conclusions:

• CASM L-type I(Ca) is decreased in large coronary arteries during early atherosclerosis due to diet-induced HC.
• The coronary microcirculation's calcium channel activity remains unaffected.
• Increased membrane free cholesterol in CASM likely causes the observed inhibition of calcium channel activity in larger arteries.