Inhibition of Jak2 phosphorylation attenuates pressure overload cardiac hypertrophy

Beckles, Daniel L.; Mascareno, Eduardo; Siddiqui, M.A.Q.

doi:10.1016/j.vph.2006.05.006

Cited by 49 publications

(35 citation statements)

References 32 publications

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“…Our observations that the redox-sensitive Ser kinase phospho-Jak2 is elevated in the Ren2 myocardium and that both telmisartan and olmesartan reduce phospho-Jak is consistent with the notion that ANG II promotes LV hypertrophy via the Jak/STAT pathway (2,22). After activation by Jak2/STAT proteins in myocardial tissue, this signaling pathway can induce an increase in angiotensinogen expression that establishes a positive feedback loop sustaining local cardiac RAS activation (22).…”

Section: Discussionsupporting

confidence: 89%

Comparative analysis of telmisartan and olmesartan on cardiac function in the transgenic (mRen2)27 rat

DeMarco

Johnson

Habibi

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Telmisartan, an angiotensin receptor blocker, may have unique benefits as it possesses partial peroxisome proliferator-activated receptor (PPAR)-␥ agonist activity in addition to antihypertensive effects. In this study, we test whether treatment with telmisartan ameliorates cardiovascular abnormalities to a greater extent than olmesartan, which has little PPAR-␥ activity. The hypertensive rodent model of tissue renin-angiotensin system activation, transgenic (mRen2)27 (Ren2) rats and their littermate Sprague-Dawley controls were used. Rats were treated with telmisartan (2 mg·kg Ϫ1 ·day Ϫ1 ), olmesartan (2.5 mg·kg Ϫ1 ·day Ϫ1 ), or vehicle via drinking water for 3 wk; these doses achieved similar blood pressure control, as measured by telemetry. Ren2 rats displayed impaired diastolic and systolic function using left ventricular (LV) pressure-volume (P-V) analysis. Load-independent diastolic indexes, including the time constant of isovolumic relaxation and the slope of the end-diastolic P-V relationship, as well as systolic indexes, including preload recruitable stroke work, the dP/dt max-end-diastolic volume (EDV) relationship, and the P-V area-EDV relationship, were elevated in Ren2 rats compared with Sprague-Dawley controls (P Ͻ 0.05). The Ren2 myocardium exhibited parallel increases in the oxidant markers NADPH oxidase and 3-nitrotyrosine. The increase in the prohypertrophic protein Jak2 in Ren2 rats was associated with cardiac structural abnormalities using light microscopic and ultrastructural analysis, which included interstitial fibrosis, cardiomyocyte and LV hypertrophy, and mitochondrial derangements. Both angiotensin receptor blockers attenuate these abnormalities to a similar extent. Our data suggest that the beneficial effect of telmisartan and olmesartan on cardiac structure and function may be predominantly pressor-related or angiotensin type 1 receptor dependent in this model of renin-angiotensin system activation. oxidative stress; left ventricular hypertrophy; peroxisome proliferatoractivated receptor-␥; Janus-activated kinase 2; AMP-activated protein kinase NUMEROUS REPORTS have demonstrated a seminal role for ANG II and the associated generation of ROS via NADPH oxidase in the development of myocardial remodeling and that angiotensin type 1 receptor (AT 1 R) blockade improves myocardial remodeling, hypertrophy, and ventricular compliance (4, 5, 31). A molecular modeling study (4) demonstrated a structural similarity between the AT 1 R blocker telmisartan and the peroxisome proliferator-activated receptor (PPAR)-␥ agonists pioglitazone and rosiglitazone. Telmisartan, to a greater extent than other angiotensin receptor blockers (ARB), acts as a partial agonist of PPAR-␥ independently of AT 1 R-blocking effects (4, 27). PPAR-␥ agonism improves insulin sensitivity and inhibits vascular oxidative stress and inflammation (11). In this regard, telmisartan reduces glucose, insulin, and triglyceride levels in a rat model of high-fat diet-induced insulin resistance (4).Some evidence suggests that PPAR-␥ a...

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Section: Discussionsupporting

confidence: 89%

Comparative analysis of telmisartan and olmesartan on cardiac function in the transgenic (mRen2)27 rat

DeMarco

Johnson

Habibi

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Among the signaling pathways that mediate cardiac hypertrophy, the JAK/STAT pathway is thought to play a pivotal role in response to various stimuli such as pressure overload, myocardial infarction, ischemia/reperfusion, cytokines, and neurohormones [8,[32][33][34][35][36][37][38].…”

Section: Stat3 and Hypertrophymentioning

confidence: 99%

STAT3 and cardiac remodeling

et al. 2010

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Multiple in vitro and in vivo studies showed that the signal transducer and activator of transcription 3 (STAT3) protein is involved in cardiomyocyte protection and hypertrophy and via paracrine pathways impacts on the non-myocyte compartment, i.e., the vasculature and the extracellular matrix. In this regard, STAT3 interacts with a broad range of cellular and molecular mechanisms that direct remodeling processes in cardiac physiology (exercise, pregnancy) and pathophysiology (pressure overload, ischemia/reperfusion, myocardial infarction, and cardiotoxic agents). STAT3 is constitutively activated by a multitude of factors including cytokines, growth factors, neurohormones, mechanical load, and ischemia. It acts as a signaling molecule, a transcription factor and according to latest observations as a mitochondrial protein involved in energy production. In this review, we provide an overview on STAT3 signaling and summarize the current understanding of the role of STAT3 for different aspects of cardiac remodeling obtained from numerous experimental and clinical studies. Finally, we highlight and critically discuss STAT3 signaling as a possible target for future therapeutic approaches in the setting of cardiac remodeling.

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“…83) and to lead to left ventricular hypertrophy in a transgenic mouse model of chronic gp130 stimulation (68). Furthermore, the JAK2 inhibitor AG490 was reported to block development of concentric hypertrophy in mice subjected to transverse aortic constriction (11). Which signaling pathway (ERK, STAT3, or PI3-kinase) links gp130 to cardiac hypertrophy is less than clear; however, that issue is irrelevant, as JAK1 and JAK2 (to a lesser extent) are critically important in gp130 signaling overall (85,143).…”

Section: Role Of Jaks In the Heartmentioning

confidence: 99%

JAK redux: a second look at the regulation and role of JAKs in the heart

Kurdi

Booz

2009

American Journal of Physiology-Heart and Circulatory Physiology

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number of type 1 receptor cytokine family members protect the heart from acute and chronic oxidative stress. This protection involves activation of two intracellular signaling cascades: the reperfusion injury salvage kinase (RISK) pathway, which entails activation of phosphatidylinositol 3-kinase (PI3-kinase) and ERK1/2, and JAK-STAT signaling, which involves activation of transcription factor signal transducer and activator of transcription 3 (STAT3). Obligatory for activation of both RISK and STAT3 by nearly all of these cytokines are the kinases JAK1 and JAK2. Yet surprisingly little is known about how JAK1 and JAK2 are regulated in the heart or how they couple to PI3-kinase activation. Although the JAKs are linked to antioxidative stress programs in the heart, we recently reported that these kinases are inhibited by oxidative stress in cardiac myocytes. In contrast, others have reported that cardiac JAK2 is activated by acute oxidative stress by an undefined process. Here we summarize recent insights into the regulation of JAK1 and JAK2. Besides oxidative stress, inhibitory regulation involves phosphorylation, nitration, and intramolecular restraints. Stimulatory regulation involves phosphorylation and adaptor proteins. The net effect of stress on JAK activity in the heart likely represents the sum of both inhibitory and stimulatory processes, along with their dynamic interaction. Thus the regulation of JAKs in the heart, once touted as the paragon of simplicity, is proving rather complicated indeed, requiring a second look. It is our contention that a better understanding of the regulation of this kinase family that is implicated in cardiac protection could translate into effective therapeutic strategies for preventing myocardial damage or repairing the injured heart. Janus kinase; oxidative stress; redox; cardiac remodeling; cytokine; cardiac myocyte A NUMBER OF TYPE 1 RECEPTOR cytokine family members, namely the interleukin (IL)-6-type cytokines [IL-6, IL-11, leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), and oncostatin M (OSM)] (40, 78, 58, 85), growth hormone (GH; Ref. 91) erythropoietin (Epo; Refs. 20,134,138), and granulocyte colony-stimulating factor (G-CSF; Refs. 26,61,62,72,159,166), as well as insulin (3,23,54,64,99,164,186), have been shown to protect the heart from acute oxidative stress, viz., ischemia-reperfusion injury. LIF (121), GH (56), Epo (77), and insulin (141) have also been reported to protect cardiac myocytes from chronic oxidative stress. Notably, a number of clinical trials have been completed or are underway assessing the efficacy of Epo or G-CSF in treating myocardial infarction and heart failure (13,87,88,93).The protective action of the type 1 receptor cytokines (see Fig. 1 for IL-6 cytokine signaling) and insulin has been shown to involve activation of two intracellular signaling cascades: 1) the reperfusion injury salvage kinase (RISK) pathway (17,27,40,41,64,66,77,99,101,102,108,121,126,128,133,134,142,156,159,160,161,166) and 2) JAK-STAT signaling (20,40,61,85,16...

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Inhibition of Jak2 phosphorylation attenuates pressure overload cardiac hypertrophy

Cited by 49 publications

References 32 publications

Comparative analysis of telmisartan and olmesartan on cardiac function in the transgenic (mRen2)27 rat

Comparative analysis of telmisartan and olmesartan on cardiac function in the transgenic (mRen2)27 rat

STAT3 and cardiac remodeling

JAK redux: a second look at the regulation and role of JAKs in the heart

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