Coronary Microvascular Dysfunction Is Associated With Augmented Lysosomal Signaling in Hypercholesterolemic Mice

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Endothelial Cell Biology

Background:

• Coronary microvascular dysfunction (CMD) from hypercholesterolemia can precede myocardial ischemia.
• Molecular mechanisms of compromised coronary microvascular function in hypercholesterolemia are not fully understood.

Purpose of the Study:

• Investigate hypercholesterolemia's effects on coronary microcirculation function and integrity in mice.
• Elucidate the underlying molecular mechanisms, focusing on endothelial cell signaling.

Main Methods:

• Hypercholesterolemic diet (Paigen's) in mice for 8 weeks.
• Echocardiography, immunofluorescence, and cell culture studies.
• Analysis of lysosomal signaling, inflammation, and oxidative stress markers.

Main Results:

• Paigen's diet induced CMD, characterized by reduced coronary blood flow and inflammation, without cardiac remodeling.
• Upregulation of lysosomal signaling pathways and transcriptional factor EB in endothelial cells was observed.
• Ezetimibe treatment ameliorated CMD, inflammation, and related molecular changes.

Conclusions:

• CMD can occur before detectable cardiac functional or structural changes in hypercholesterolemia.
• Transcriptional factor EB-mediated lysosomal signaling in endothelial cells plays a protective role in CMD.
• Ezetimibe shows potential in mitigating hypercholesterolemia-induced CMD.