Hepatic JAK2 protects against atherosclerosis through circulating IGF-1

Area of Science:

• Cardiovascular Biology
• Metabolic Disease Research
• Inflammation and Immunology

Background:

• Atherosclerosis is a complex metabolic and inflammatory disease.
• The liver plays a critical role in lipid metabolism and inflammation.
• Janus kinase 2 (JAK2) is implicated in hepatic lipid metabolism and inflammation, but its role in atherosclerosis is unclear.

Purpose of the Study:

• To investigate the precise effects of hepatic JAK2 on the development of atherosclerosis.
• To elucidate the molecular mechanisms by which hepatic JAK2 influences atherogenesis.

Main Methods:

• Utilized atherosclerosis-prone mouse models with hepatic Jak2 deficiency.
• Analyzed atherosclerotic plaque composition, specifically macrophage and smooth muscle cell content.
• Investigated the role of JAK2 in hepatic growth hormone signaling and its impact on circulating IGF-1 levels.
• Assessed the therapeutic potential of restoring IGF-1 levels pharmacologically and genetically.

Main Results:

• Hepatic Jak2 deficiency accelerated atherosclerosis, characterized by increased plaque macrophages and reduced smooth muscle cell content.
• Hepatic Jak2 deficiency led to reduced circulating IGF-1 levels, causally linked to exacerbated atherosclerosis.
• Restoration of IGF-1 levels, either pharmacologically or genetically, attenuated the atherosclerotic burden.

Conclusions:

• Hepatic JAK2 plays a protective role in atherogenesis.
• This protective effect is mediated through JAK2's regulation of hepatic growth hormone signaling and subsequent circulating IGF-1 levels.
• Identified a novel liver-centric mechanism contributing to atheroprotection.