Deletion of interleukin-6 prevents cardiac inflammation, fibrosis and dysfunction without affecting blood pressure in angiotensin II-high salt-induced hypertension

Gónzalez, Germán E.; Rhaleb, Nour Eddine; D’Ambrosio, Martin A.; Nakagawa, Pablo; Liu, Yunhe; Leung, Pablo; Dai, Xiangguo; Yang, Xiao Ping; Peterson, Edward L.; Carretero, Oscar A.

doi:10.1097/hjh.0000000000000358

Cited by 85 publications

(69 citation statements)

References 40 publications

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“…Previous studies have suggested an involvement of IL-6 in inflammation and dysfunction induced by Ang II, 26 however, its role in cardiac myocyte hypertrophy triggered by common inducers of myocyte hypertrophy remains unclear. Moreover, such observations have rarely been tested in adult cardiac myocytes isolated from IL-6 −/− mice.…”

Section: Discussionmentioning

confidence: 96%

Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction

Zhao

Cheng

Jin

et al. 2016

Circulation Research

191

148

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Rationale The role of interleukin (IL)-6 in the pathogenesis of cardiac myocyte hypertrophy remains controversial. Objective To conclusively determine whether IL-6 signaling is essential for the development of pressure overload-induced left ventricular (LV) hypertrophy, and to elucidate the underlying molecular pathways. Methods and Results Wild-type (WT) and IL-6 knockout (IL-6−/−) mice underwent sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Serial echocardiograms and terminal hemodynamic studies revealed attenuated LV hypertrophy and superior preservation of LV function in IL-6−/− mice after TAC. The extents of LV remodeling, fibrosis, and apoptosis were reduced in IL-6−/− hearts after TAC. Transcriptional and protein assays of myocardial tissue identified CaMKII and STAT3 activation as important underlying mechanisms during cardiac hypertrophy induced by TAC. The involvement of these pathways in myocyte hypertrophy was verified in isolated cardiac myocytes from WT and IL-6−/− mice exposed to pro-hypertrophy agents. Furthermore, overexpression of CaMKII in H9c2 cells increased STAT3 phosphorylation, and exposure of H9c2 cells to IL-6 resulted in STAT3 activation that was attenuated by CaMKII inhibition. Together these results identify the importance of CaMKII-dependent activation of STAT3 during cardiac myocyte hypertrophy via IL-6 signaling. Conclusions Genetic deletion of IL-6 attenuates TAC-induced LV hypertrophy and dysfunction, indicating a critical role played by IL-6 in the pathogenesis of LV hypertrophy in response to pressure overload. CaMKII plays an important role in IL-6-induced STAT3 activation and consequent cardiac myocyte hypertrophy. These findings may have significant therapeutic implications for LV hypertrophy and failure in patients with hypertension.

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Section: Discussionmentioning

confidence: 96%

Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction

Zhao

Cheng

Jin

et al. 2016

Circulation Research

191

148

View full text Add to dashboard Cite

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“…The pro-inflammatory cytokines which were induced by pressure overload are highly pleiotropic, not only cause myocardial hypertrophy but also regulate the fibrotic process via several distinct pathways [9,[16][17][18] . In our experiments, the levels of the pro-inflammatory factors IL-1, IL-6 and TNF-α were significantly increased after AB and peaked at 2 weeks after AB, followed by decreased levels thereafter.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Toll-like receptor 5 deficiency attenuates interstitial cardiac fibrosis and dysfunction induced by pressure overload by inhibiting inflammation and the endothelial–mesenchymal transition

Liu

Liao

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Vascular dysfunction, characterized by the endothelial-to-mesenchymal transition (EndMT), contributes to the development of cardiac fibrosis induced by pressure overload. Toll-like receptor (TLR)5 is a member of the TLR family that is expressed on not only immune cells but also nonimmune cells including cardiomyocytes and vascular endothelial cells. The level of TLR5 expression on endothelial cells is low under normal circumstances but is increased in response to stimuli such as pressure overload. The aim of this study was to investigate the importance of TLR5 in cardiac endothelial dysfunction during the development of cardiac fibrosis induced by pressure overload. Global TLR5-deficient mice and wild-type littermates underwent aortic banding (AB) for 8weeks to induce cardiac fibrosis, hypertrophy and dysfunction. The deficiency of TLR5 in this model exerted no basal effects but attenuated the cardiac fibrosis, hypertrophy and dysfunction induced by pressure overload. AB-induced endothelial TLR5 activation enhanced the development of cardiac fibrosis independent of cardiomyocyte hypertrophy and triggered left ventricular dysfunction. TLR5-deficient mice also exhibited ameliorated myocardial pro-inflammatory cytokine expression and macrophage infiltration and inhibited the EndMT, all of which contribute to the development of cardiac fibrosis. These findings suggest that TLR5 triggers inflammatory responses and promotes the EndMT, which may be an important mechanism underlying the promotion of cardiac fibrosis and left ventricular dysfunction during pressure overload.

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“…While inflammatory cells have long been described to infiltrate the vasculature and organs such as the kidney and heart in HTN 31–33 , the evidence supporting IC infiltration and accumulation in the brain parenchyma are fewer 25, 34–36 . All these observations have led us to hypothesize that the BM exhibits a pro-inflammatory state in HTN, characterized by increased inflammatory cells and cytokines.…”

Section: Introductionmentioning

confidence: 99%

Involvement of Bone Marrow Cells and Neuroinflammation in Hypertension

Santisteban

Ahmari

Carvajal

et al. 2015

Circulation Research

147

175

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Rationale Microglial activation in autonomic brain regions is a hallmark of neuroinflammation in neurogenic hypertension (HTN). Despite evidence that an impaired sympathetic nerve activity supplying the bone marrow (BM) increases inflammatory cells and decreases angiogenic cells, little is known about the reciprocal impact of BM-derived inflammatory cells on neuroinflammation in HTN. Objective Test the hypothesis that pro-inflammatory BM cells from hypertensive animals contribute to neuroinflammation and HTN via a brain-BM interaction. Methods and Results Following BM ablation in spontaneously hypertensive rats (SHR), and reconstitution with normotensive Wistar-Kyoto (WKY) rat BM, the resultant chimeric SHR displayed significant reduction in mean arterial pressure (MAP) associated with attenuation of both central and peripheral inflammation. In contrast, an elevated MAP along with increased central and peripheral inflammation was observed in chimeric WKY rats reconstituted with SHR BM. Oral treatment with minocycline, an inhibitor of microglial activation, attenuated HTN in both the SHR and chronic angiotensin II (Ang II)-infused rats. This was accompanied by decreased sympathetic drive and inflammation. Furthermore, in chronic Ang II-infused rats, minocycline prevented extravasation of BM-derived cells to the hypothalamic paraventricular nucleus (PVN), presumably via a mechanism of decreased C-C chemokine ligand 2 levels in the cerebrospinal fluid. Conclusions The BM contributes to HTN by increasing peripheral inflammatory cells and their extravasation into the brain. Minocycline is an effective therapy to modify neurogenic components of HTN. These observations support the hypothesis that BM-derived cells are involved in neuroinflammation, and targeting them may be an innovative strategy for neurogenic resistant HTN therapy.

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Deletion of interleukin-6 prevents cardiac inflammation, fibrosis and dysfunction without affecting blood pressure in angiotensin II-high salt-induced hypertension

Cited by 85 publications

References 40 publications

Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction

Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction

Toll-like receptor 5 deficiency attenuates interstitial cardiac fibrosis and dysfunction induced by pressure overload by inhibiting inflammation and the endothelial–mesenchymal transition

Involvement of Bone Marrow Cells and Neuroinflammation in Hypertension

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