Hepatic JAK2 protects against atherosclerosis through circulating IGF-1
Tharini Sivasubramaniyam, … , Clinton S. Robbins, Minna Woo
Tharini Sivasubramaniyam, … , Clinton S. Robbins, Minna Woo
Published July 20, 2017
Citation Information: JCI Insight. 2017;2(14):e93735. https://doi.org/10.1172/jci.insight.93735.
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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 7

Restoration of IGF-1 reduces circulating growth hormone levels and attenuates atherosclerotic plaque burden in L-Jak2–/–ApoE–/– mice.

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Restoration of IGF-1 reduces circulating growth hormone levels and atten...
To restore circulating IGF-1 levels by pharmacologic means, vehicle (saline + 10 mmol/L HCl) or human long R3 IGF-1 (1.0 mg/kg/d), a biologically active IGF-1 analog, was administered by s.c. osmotic pumps into 8-week-old L-Jak2–/–ApoE–/– mice and L-Jak2+/+ApoE–/– littermate controls for 12 weeks while being fed an atherogenic diet containing 0.2% cholesterol. (A) Serum growth hormone (GH) levels were measured in vehicle-infused L-Jak2+/+ApoE–/– (n = 7), IGF-1–infused L-Jak2+/+ApoE–/– (n = 4), vehicle-infused L-Jak2–/–ApoE–/– (n = 7), and IGF-1–infused L-Jak2–/–ApoE–/– (n = 6) mice. (B) Representative photographs of en face oil red O (ORO) staining and quantification of atherosclerotic plaque area in descending aortas of vehicle-infused L-Jak2+/+ApoE–/– (n = 7), IGF-1–infused L-Jak2+/+ApoE–/– (n = 4), vehicle-infused L-Jak2–/–ApoE–/– (n = 8), and IGF-1–infused L-Jak2–/–ApoE–/– (n = 6) mice. Scale bar: 1 cm. (C) Representative images of longitudinal sections from the aortic arch of vehicle-infused L-Jak2+/+ApoE–/– (n = 6), IGF-1–infused L-Jak2+/+ApoE–/– (n = 4), vehicle-infused L-Jak2–/–ApoE–/– (n = 8), and IGF-1–infused L-Jak2–/–ApoE–/– (n = 5) mice 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. Scale bar: 200 μm. (D) Representative images of the lesser curvature of longitudinal aortic arch sections from vehicle-infused L-Jak2+/+ApoE–/– (n = 5), IGF-1–infused L-Jak2+/+ApoE–/– (n = 2), vehicle-infused L-Jak2–/–ApoE–/– mice (n = 8), and IGF-1–infused L-Jak2–/–ApoE–/– (n = 5) mice immunostained with antibody against Mac-3 and quantification of positively stained area. Scale bar: 100 μm. To restore circulating IGF-1 using a genetic approach, L-Jak2–/–ApoE–/– and L-Jak2+/+ApoE–/– controls expressing an Igf1 transgene in the liver (L-Jak2–/–ApoE–/–Tg-Igf1+ or L-Jak2+/+ApoE–/–Tg-Igf1+, respectively) and those not expressing the transgene (L-Jak2–/–ApoE–/–Tg-Igf1– or L-Jak2+/+ApoE–/–Tg-Igf1–, respectively) were fed an atherogenic diet containing 0.2% cholesterol for 13–14 weeks, starting at 8 weeks of age. (E) Representative photographs of en face ORO staining and quantification of atherosclerotic plaque area in descending aortas of L-Jak2+/+ApoE–/–Tg-Igf1– (n = 7), L-Jak2+/+ApoE–/–Tg-Igf1+ (n = 9), L-Jak2–/–ApoE–/–Tg-Igf1– (n = 8), and L-Jak2–/–ApoE–/–Tg-Igf1+ (n = 11) mice. (F) Serum GH levels were measured in L-Jak2+/+ApoE–/–Tg-Igf1– (n = 4), L-Jak2+/+ApoE–/–Tg-Igf1+ (n = 5), L-Jak2–/–ApoE–/–Tg-Igf1– (n = 3), and L-Jak2–/–ApoE–/–Tg-Igf1+ (n = 8) mice. 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 using One-way ANOVA with Newman-Keuls post-hoc test. *P < 0.05, ***P < 0.001.