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 92 publications

(74 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

207

154

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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

207

154

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“…In a model of rheumatoid arthritis, Bmx was shown to act in a kinaseindependent manner downstream of, or at the same level as, TGF-β activated kinase 1 (TAK1) to mediate inflammatory cytokine signaling, including IL-8 (14). Recently, it was shown that deletion of IL-6 prevents cardiac inflammation, fibrosis, and dysfunction after Ang II (30). Our results showed that inactivation of Bmx abolished the Ang II-induced increase in IL-6 and IL-8, placing Bmx upstream of the inflammatory cascade.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling

Holopainen

Räsänen

Anisimov

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cardiac hypertrophy accompanies many forms of heart disease, including ischemic disease, hypertension, heart failure, and valvular disease, and it is a strong predictor of increased cardiovascular morbidity and mortality. Deletion of bone marrow kinase in chromosome X (Bmx), an arterial nonreceptor tyrosine kinase, has been shown to inhibit cardiac hypertrophy in mice. This finding raised the possibility of therapeutic use of Bmx tyrosine kinase inhibitors, which we have addressed here by analyzing cardiac hypertrophy in gene-targeted mice deficient in Bmx tyrosine kinase activity. We found that angiotensin II (Ang II)-induced cardiac hypertrophy is significantly reduced in mice deficient in Bmx and in mice with inactivated Bmx tyrosine kinase compared with WT mice. Genome-wide transcriptomic profiling showed that Bmx inactivation suppresses myocardial expression of genes related to Ang II-induced inflammatory and extracellular matrix responses whereas expression of RNAs encoding mitochondrial proteins after Ang II administration was maintained in Bmx-inactivated hearts. Very little or no Bmx mRNA was expressed in human cardiomyocytes whereas human cardiac endothelial cells expressed abundant amounts. Ang II stimulation of endothelial cells increased Bmx phosphorylation, and Bmx gene silencing inhibited downstream STAT3 signaling, which has been implicated in cardiac hypertrophy. Furthermore, activation of the mechanistic target of rapamycin complex 1 pathway by Ang II treatment was decreased in the Bmx-deficient hearts. Our results demonstrate that inhibition of the cross-talk between endothelial cells and cardiomyocytes by Bmx inactivation suppresses Ang II-induced signals for cardiac hypertrophy. These results suggest that the endothelial Bmx tyrosine kinase could provide a target to attenuate the development of cardiac hypertrophy.

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

Cited by 92 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

Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling

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

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