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  • The following are the supplementary data related to


    The following are the supplementary data related to this article.
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    Introduction Heart failure (HF) is a debilitating disease with high rates of mortality. The pathogenesis underlying HF is complex but is mostly related to cardiac remodeling caused by cardiac myocyte hypertrophy and re-expression of the fetal gene program leading to myocardial fibrosis [[1], [2], [3]]. Cardiac hypertrophy is a physiological compensatory process of the heart to adapt to various pathological conditions demanding increased cardiac output. However, during maladaptive myocardial hypertrophy increased size of cardiac myocytes is accompanied of mechanic and metabolic alterations resulting in N-octanoyl-L-Homoserine lactone dysfunction. Maladaptive hypertrophy is a frequent consequence of sustained vascular hypertension, involving Angiotensin II (Ang II) [4]. Ang II is a key executor of the renin-angiotensin-aldosterone system (RAAS), which is reported to be highly associated with increased risk of myocardial hypertrophy and HF [2,[5], [6], [7]] Indeed, chronic pressure overload could cause cardiac hypertrophy, which is related to the autocrine release of Ang II from the myocardium in response to abnormal harmful stress [8,9]. Accumulating evidences including ours proved that extra activated oxidative stress participates in Ang II-induced cardiac myopathy [[10], [11], [12], [13]]. However, it is still not fully understood how Ang II influences cardiac hypertrophy and remodeling. Investigating the downstream signals of Ang II is of potential importance because it can provide new approaches for clinical therapy of cardiovascular diseases. The transcription factor NF-E2-related factor 2 (Nrf2) belongs to the Cap‘n’collar subfamily of basic region leucine zipper transcription factors which is known to mediate protection against drug and oxidative-induced cell stress [14]. The Nrf2 pathway is involved in the cellular response to multiple diseases such as cancer [15,16], diabetes [17,18] and cardiovascular disease [[19], [20], [21]]. Nrf2 translocates to the nucleus upon oxidative stress, where it binds to the promoter of, among others, antioxidant genes, such as superoxide dismutase 1 (SOD1), glutathione transferases, glutamate cysteine ligase and heme oxygenase-1 (HO-1) [22]. Overexpression of Nrf2 has been proved to be cytoprotective in multiple human diseases, whereas Nrf2 gene deletion exacerbates the sensitivity to tissue injury [[22], [23], [24], [25], [26]]. Moreover, recent research also proved that Nrf2 is involved in Ang II-induced as well as hemodynamic stress-induced hypertrophic cardiomyopathy [20,27,28]. Finally, Nrf2 genetic deletion in mice has been shown to induce cardiac dysfunction and hypertrophy [29]. These results delineate a central role for Nrf2 in preventing the heart from oxidative stress-related damage. However, the potential crosstalk between cardiac remodeling and Nrf2 still remains poorly characterized. Interleukin-6 (IL-6) is a pleiotropic cytokine that is produced by and acts on several tissues throughout the body including cardiomyocytes. Studies including our previous research proved that IL-6 is involved in Ang II-induced hypertensive cardiac damage [10,[30], [31], [32], [33]]. The cytokines of the IL-6 family are activated in response to the phosphorylation of signal transducer and activator of transcription 3 (STAT3) [34], which promotes the transcription of inflammatory cytokines. There is cooperation of oxidative stress and inflammation induced by STAT3 activation in experimental mice hearts [35]. Our previous research also suggests alleviated oxidative stress in the heart of mice deficient for IL-6 during Ang II-induced cardiac injury [10,30]. Moreover, it is reported that IL-6 promoter contains an antioxidant response element (ARE) and its expression can be stimulated by Nrf2 in β-cell of pancreas [36], implying regulatory links between these signaling pathways. However, the link between Nrf2-associated mitigation of oxidative stress and IL-6/STAT3-mediated stimulation of inflammation has not been tested.