Hepatic JAK2 protects against atherosclerosis through circulating IGF-1
Tharini Sivasubramaniyam, Stephanie A. Schroer, Angela Li, Cynthia T. Luk, Sally Yu Shi, Rickvinder Besla, David W. Dodington, Adam H. Metherel, Alex P. Kitson, Jara J. Brunt, Joshua Lopes, Kay-Uwe Wagner, Richard P. Bazinet, Michelle P. Bendeck, Clinton S. Robbins, Minna Woo
Tharini Sivasubramaniyam, Stephanie A. Schroer, Angela Li, Cynthia T. Luk, Sally Yu Shi, Rickvinder Besla, David W. Dodington, Adam H. Metherel, Alex P. Kitson, Jara J. Brunt, Joshua Lopes, Kay-Uwe Wagner, Richard P. Bazinet, Michelle P. Bendeck, Clinton S. Robbins, Minna Woo
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Research Article Metabolism Vascular biology

Hepatic JAK2 protects against atherosclerosis through circulating IGF-1

Abstract

Atherosclerosis is considered both a metabolic and inflammatory disease; however, the specific tissue and signaling molecules that instigate and propagate this disease remain unclear. The liver is a central site of inflammation and lipid metabolism that is critical for atherosclerosis, and JAK2 is a key mediator of inflammation and, more recently, of hepatic lipid metabolism. However, precise effects of hepatic Jak2 on atherosclerosis remain unknown. We show here that hepatic Jak2 deficiency in atherosclerosis-prone mouse models exhibited accelerated atherosclerosis with increased plaque macrophages and decreased plaque smooth muscle cell content. JAK2’s essential role in growth hormone signalling in liver that resulted in reduced IGF-1 with hepatic Jak2 deficiency played a causal role in exacerbating atherosclerosis. As such, restoring IGF-1 either pharmacologically or genetically attenuated atherosclerotic burden. Together, our data show hepatic Jak2 to play a protective role in atherogenesis through actions mediated by circulating IGF-1 and, to our knowledge, provide a novel liver-centric mechanism in atheroprotection.

Authors

Tharini Sivasubramaniyam, Stephanie A. Schroer, Angela Li, Cynthia T. Luk, Sally Yu Shi, Rickvinder Besla, David W. Dodington, Adam H. Metherel, Alex P. Kitson, Jara J. Brunt, Joshua Lopes, Kay-Uwe Wagner, Richard P. Bazinet, Michelle P. Bendeck, Clinton S. Robbins, Minna Woo

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Figure 1

Accelerated atherosclerosis with hepatic Jak2–deficiency.

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Accelerated atherosclerosis with hepatic Jak2–deficiency. ApoE-null mice...
ApoE-null mice with hepatic Jak2 deficiency (L-Jak2–/–ApoE–/–) and littermate controls (L-Jak2+/+ApoE–/–) were fed an atherogenic diet containing 0.2% cholesterol for 12 weeks, starting at 6 weeks of age. (A) Representative photographs of en face oil red O (ORO) staining and quantification of atherosclerotic plaque area in descending aortas of L-Jak2–/–ApoE–/– mice (n = 17) and control L-Jak2+/+ApoE–/– mice (n = 13). Scale bar: 1 cm. (B) Representative images of longitudinal sections from the aortic arch of L-Jak2–/–ApoE–/– mice (n = 15) and control L-Jak2+/+ApoE–/– mice (n = 10) stained with H&E and quantification of lesion size at the lesser curvature. B, brachiocephalic artery; C, left common carotid; S, subclavian artery; L, lesser curvature. Arrow indicates necrotic core. Scale bar: 200 μm. (C and D) Representative images of the lesser curvature of longitudinal aortic arch sections from L-Jak2–/–ApoE–/– (n = 10–14) and control L-Jak2+/+ApoE–/– (n = 8–9) mice immunostained with antibody against Mac-3 and α-smooth muscle actin (α-SMA) and quantification of positively stained area expressed as an absolute number or percentage. Scale bars: 100 μm. In each of the panels, each dot in the scatter plot indicates an individual animal. Data represent mean ± SEM. Differences between groups were analyzed for statistical significance by Student unpaired t test. *P < 0.05, **P < 0.01.