Coronary Microvascular Dysfunction is Associated with Augmented Lysosomal Signaling in Hypercholesterolemic Mice

Area of Science:

• Cardiovascular Biology
• Cellular and Molecular Medicine
• Pharmacology

Background:

• Coronary microvascular dysfunction (CMD) from hypercholesterolemia can precede myocardial ischemia, but underlying molecular mechanisms are unclear.
• Understanding these pathways is crucial for preventing cardiac damage in high cholesterol conditions.

Purpose of the Study:

• To investigate the impact of hypercholesterolemia on coronary microvascular function and integrity in mice.
• To elucidate the molecular mechanisms, particularly lysosomal signaling in endothelial cells (ECs), involved in hypercholesterolemia-induced CMD.

Main Methods:

• Mice were fed a hypercholesterolemic diet (Paigen's diet, PD) for 8 weeks.
• Echocardiography, immunofluorescence, and cell culture studies with 7-ketocholesterol (7K) were employed.
• Effects of ezetimibe treatment on CMD and molecular pathways were assessed.

Main Results:

• PD induced CMD, characterized by reduced coronary blood flow and reserve, without cardiac remodeling.
• Inflammation in coronary arterioles and increased myocardial inflammatory cell infiltration were observed, paralleling lysosomal signaling activation in ECs.
• Ezetimibe treatment ameliorated CMD and inflammation; in MCECs, ezetimibe attenuated 7K-induced mitochondrial ROS and inflammation while enhancing TFEB activation.

Conclusions:

• Hypercholesterolemia-induced CMD can occur independently of overt cardiac dysfunction or remodeling.
• TFEB-mediated lysosomal signaling in ECs plays a protective role against CMD development.
• Ezetimibe demonstrates potential therapeutic benefits by modulating EC inflammation and lysosomal pathways in hypercholesterolemia.