Hepatic JAK2 protects against atherosclerosis through circulating IGF-1

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

doi:10.1172/jci.insight.93735

Cited by 15 publications

(19 citation statements)

References 80 publications

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“…Elevated IGF-1 levels in the circulation not only decreased plaque burden, but also induced phenotypic changes in plaques, represented by a decrease of macrophages, attenuated proinflammatory cytokine expression, lowered oxidative stress, less frequent apoptosis, and increased presence of smooth muscle cells and collagen [45,96,97]. Vice versa, low levels of circulating IGF-1 in the 6T congenic mouse [98] and in the liver-specific IGF-1 knockout mouse [93] was associated with enhanced inflammatory phenotype and increased atherosclerotic burden. These observations suggest that IGF-1 may reduce inflammation and promote a more stable plaque phenotype, underscoring IGF-1's therapeutic potential to prevent clinical events caused by plaque vulnerability.…”

Section: Atheroprotective Effects Of Igf-1 In Animal Models Of Atheromentioning

confidence: 99%

“…Since this report, we and others have confirmed that systemic IGF-1 levels inversely correlate with atherosclerotic burden [45], consistent with atheroprotective effects of IGF-1. Sivasubramaniyam et al [93] generated Apoe-null mice with hepatic Jak2 deficiency, which impairs the GH signaling pathway, therefore these mice have significantly lower circulating IGF-1 levels than hepatic Jak2-wild type mice [93]. These animals had significantly accelerated atherosclerosis and the causal relation between low IGF-1 and atherosclerosis was confirmed by supplementing IGF-1 by continuous infusion (at a dose that does not influence glucose tolerance or insulin sensitivity, however reverses GH levels down as low as Jak2-wild type mice [93]) or by overexpression of IGF-1 (by crossbreeding to hepatic IGF-1 overexpression mice in which serum IGF-1 levels were 2.5-fold higher than no-overexpression controls [94]) in hepatocytes of Jak2-deficient mice [93].…”

Section: Atheroprotective Effects Of Igf-1 In Animal Models Of Atheromentioning

confidence: 99%

“…Sivasubramaniyam et al [93] generated Apoe-null mice with hepatic Jak2 deficiency, which impairs the GH signaling pathway, therefore these mice have significantly lower circulating IGF-1 levels than hepatic Jak2-wild type mice [93]. These animals had significantly accelerated atherosclerosis and the causal relation between low IGF-1 and atherosclerosis was confirmed by supplementing IGF-1 by continuous infusion (at a dose that does not influence glucose tolerance or insulin sensitivity, however reverses GH levels down as low as Jak2-wild type mice [93]) or by overexpression of IGF-1 (by crossbreeding to hepatic IGF-1 overexpression mice in which serum IGF-1 levels were 2.5-fold higher than no-overexpression controls [94]) in hepatocytes of Jak2-deficient mice [93]. Svensson et al [95] investigated diet-induced fatty streak formation in liver-specific IGF-1 inactivation mice (LI-IGF-1−/− mice), in which the serum IGF-1 level is lower than wild-type control mice by 80 % [95].…”

Section: Atheroprotective Effects Of Igf-1 In Animal Models Of Atheromentioning

confidence: 99%

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IGF-1 and cardiovascular disease

Higashi

Gautam

Delafontaine

et al. 2019

Growth Hormone & IGF Research

108

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Atherosclerosis is an inflammatory arterial pathogenic condition, which leads to ischemic cardiovascular diseases, such as coronary artery disease and myocardial infarction, stroke, and peripheral arterial disease. Atherosclerosis is a multifactorial disorder and its pathophysiology is highly complex. Changes in expression of multiple genes coupled with environmental and lifestyle factors initiate cascades of adverse events involving multiple types of cells (e.g. vascular endothelial cells, smooth muscle cells, and macrophages). IGF-1 is a pleiotropic factor, which is found in the circulation (endocrine IGF-1) and is also produced locally in arteries (endothelial cells and smooth muscle cells). IGF-1 exerts a variety of effects on these cell types in the context of the pathogenesis of atherosclerosis. In fact, there is an increasing body of evidence suggesting that IGF-1 has beneficial effects on the biology of atherosclerosis. This review will discuss recent findings relating to clinical investigations on the relation between IGF-1 and cardiovascular disease and basic research using animal models of atherosclerosis that have elucidated some of the mechanisms underlying atheroprotective effects of IGF-1.

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Section: Atheroprotective Effects Of Igf-1 In Animal Models Of Atheromentioning

confidence: 99%

Section: Atheroprotective Effects Of Igf-1 In Animal Models Of Atheromentioning

confidence: 99%

Section: Atheroprotective Effects Of Igf-1 In Animal Models Of Atheromentioning

confidence: 99%

See 1 more Smart Citation

IGF-1 and cardiovascular disease

Higashi

Gautam

Delafontaine

et al. 2019

Growth Hormone & IGF Research

108

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“…Another possible explanations for the association between IGF-1 and insulin resistance are driven by chronic in ammatory. Low levels of IGF-1 in the C3H.6T mice [18]and in the liver-speci c IGF-1 knockout mouse [19]were associated with enhanced in ammatory phenotype. On the contrary, elevated IGF-1 levels could attenuate the anti-in ammatory effects and the lowered oxidative stress [19][20][21].…”

Section: Discussionmentioning

confidence: 92%

“…Low levels of IGF-1 in the C3H.6T mice [18]and in the liver-speci c IGF-1 knockout mouse [19]were associated with enhanced in ammatory phenotype. On the contrary, elevated IGF-1 levels could attenuate the anti-in ammatory effects and the lowered oxidative stress [19][20][21]. Meanwhile, in ammatory factors and chronic in ammatory responses play an important role in the occurrence and development of insulin resistance [22].…”

Section: Discussionmentioning

confidence: 92%

Association Between Insulin-like Growth Factor 1 and Insulin Resistance in Obese Prepubertal Boys: A Cross-sectional Study

Kuang¹,

Zhang²,

et al. 2020

Preprint

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Background: As one of the most common features of obesity, insulin resistance is central to the pathogenesis of the metabolic syndrome. Low insulin-like growth factor 1(IGF-1) levels have been proven to be associated with many traditional cardiovascular risk factors, but it still remains controversy with the relationship between IGF-1 and insulin resistance. Accordingly, the main purpose of this study is to investigate the relationship between IGF-1 and insulin resistance in obese prepubertal boys.Methods: We used whole body insulin sensitivity index (WBISI) to represent insulin resistance. 70 obese prepubertal boys were included in this study, and the obese subjects were divided into two groups by using 1.285 as a threshold value for WBISI. Clinical examination and laboratory examinations were assessed for all participants.Results: Among obese boys, the group of children with WBISI ≤1.285 had lower IGF-1 standard deviation scores (SDS) (p = 0.021) than WBISI >1.285 group. The results of multivariate stepwise regression analysis show that WBISI was positively correlated with IGF-1 SDS (β =1.726, p = 0.002) after adjusting for traditional cardiovascular risk factors.Conclusion: IGF-1 SDS was negatively associated with insulin resistance in obese prepubertal boys, independent of other traditional cardiovascular disease risk markers.

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Einfluss der klonalen Hämatopoese auf nicht-hämatologische Erkrankungen und Alterungsprozesse

Rieger

2022

Innere Medizin

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Das Auftreten von klonaler Hämatopoese, ausgelöst durch erworbene somatische Mutationen in leukämieassoziierten Genen in Blutstammzellen, ist weit verbreitet und steigt mit zunehmendem Alter. Neben einem erhöhten Risiko, eine myeloische Neoplasie zu entwickeln, wurde in den letzten Jahren ein unerwarteter, kausaler Zusammenhang zwischen klonaler Hämatopoese und Herz-Kreislauf-Erkrankungen gefunden. Klonale Hämatopoese präsentiert sich als neuer, unabhängiger und hoher Risikofaktor für kardiovaskuläre Erkrankungen wie Atherosklerose, koronare Herzkrankheit, Herzinsuffizienz, Aortenklappenstenose sowie Schlaganfall und sollte aus medizinischer Sicht nicht mehr ignoriert werden. Die weltweit intensive Forschung nach Assoziationen von klonaler Hämatopoese mit anderen altersbedingten Leiden und mit Infektionskrankheiten findet immer mehr Erkrankungen, die durch die Anwesenheit mutierter Blutzellen beeinflusst werden. Aktuelle Erkenntnisse beschreiben einen fatalen Kreislauf, der ausgelöst durch somatische Blutzellmutationen den Krankheitsverlauf assoziierter Erkrankungen proinflammatorisch verstärkt und sich auf eine Vergrößerung des mutierten Blutzellklons auswirkt. Erste experimentelle Therapieansätze, um diesen Teufelskreis zu brechen, werden hier diskutiert. Die kausalen Zusammenhänge und Pathomechanismen stehen jetzt im Zentrum der Forschung, um Risikoabschätzungen und therapeutische Maßnahmen zum Wohle der Patient*innen rasch auf den Weg bringen zu können.

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Hepatic JAK2 protects against atherosclerosis through circulating IGF-1

Cited by 15 publications

References 80 publications

IGF-1 and cardiovascular disease

IGF-1 and cardiovascular disease

Association Between Insulin-like Growth Factor 1 and Insulin Resistance in Obese Prepubertal Boys: A Cross-sectional Study

Einfluss der klonalen Hämatopoese auf nicht-hämatologische Erkrankungen und Alterungsprozesse

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