MRTF-A regulates proliferation and survival properties of pro-atherogenic macrophages

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Immunology

Background:

• Promoter polymorphism of myocardin-related transcription factor A (MRTF-A) is linked to coronary atherosclerosis.
• The specific role of MRTF-A in atherosclerosis development is not fully understood.
• Macrophages are key players in atherosclerosis, and their proliferation and survival are atherogenic.

Purpose of the Study:

• To investigate the role of macrophagic MRTF-A in the pathogenesis of atherosclerosis.
• To determine if MRTF-A overexpression in macrophages exacerbates atherosclerosis.
• To elucidate the mechanisms by which MRTF-A influences macrophage function in atherosclerosis.

Main Methods:

• Human carotid atherosclerotic plaques were analyzed for MRTF-A expression in macrophages.
• ApoE null MRTF-A transgenic mice (ApoE-/-/MRTF-A tg/+) were generated for specific overexpression of human MRTF-A in monocytes/macrophages.
• Mice were fed a normal diet to assess atherosclerosis progression.
• In vitro and in vivo experiments evaluated macrophage proliferation, apoptosis, and cyclin-dependent kinase inhibitor expression.

Main Results:

• MRTF-A was highly expressed in lesional macrophages within human atherosclerotic plaques.
• ApoE-/-/MRTF-A tg/+ mice exhibited aggravated atherosclerosis and increased accumulation of lesional macrophages in the aortic sinus compared to controls.
• MRTF-A was found to promote macrophage proliferation and inhibit apoptosis, while downregulating cyclin-dependent kinase inhibitors.

Conclusions:

• MRTF-A significantly modulates the functional properties of pro-atherogenic macrophages.
• Overexpression of MRTF-A in macrophages exacerbates atherosclerosis progression.
• MRTF-A plays a critical pathological role in the development and advancement of atherosclerosis.