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      Aliskiren ameliorates pressure overload-induced heart hypertrophy and fibrosis in mice

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          Abstract

          Aim:

          Aliskiren (ALK) is a renin inhibitor that has been used in the treatment of hypertension. The aim of this study was to determine whether ALK could ameliorate pressure overload-induced heart hypertrophy and fibrosis, and to elucidate the mechanisms of action.

          Methods:

          Transverse aortic constriction (TAC) was performed in mice to induce heart pressure overload. ALK (150 mg·kg −1·d −1, po), the autophagy inhibitor 3-methyladenine (10 mg·kg −1 per week, ip) or the PKCβI inhibitor LY333531 (1 mg·kg −1·d- 1, po) was administered to the mice for 4 weeks. Heart hypertrophy, fibrosis and function were evaluated based on echocardiography, histological and biochemical measurements. Mechanically stretched cardiomyocytes of rats were used for in vitro experiments. The levels of signaling proteins were measured using Western blotting, while the expression of the relevant genes was analyzed using real-time QRT-PCR.

          Results:

          TAC induced marked heart hypertrophy and fibrosis, accompanied by high levels of Ang II in plasma and heart, and by PKCβI/α and ERK1/2 phosphorylation in heart. Meanwhile, TAC induced autophagic responses in heart, i.e. increases in autophagic structures, expression of Atg5 and Atg16 L1 mRNAs and LC3-II and Beclin-1 proteins. These pathological alterations in TAC-mice were significantly ameliorated or blocked by ALK administration. In TAC-mice, 3-methyladenine administration also ameliorated heart hypertrophy, fibrosis and dysfunction, while LY333531 administration inhibited ERK phosphorylation and autophagy in heart. In mechanically stretched cardiomyocytes, CGP53353 (a PKCβI inhibitor) prevented ERK phosphorylation and autophagic responses, while U0126 (an ERK inhibitor) blocked autophagic responses.

          Conclusion:

          ALK ameliorates heart hypertrophy, fibrosis and dysfunction in the mouse model in setting of chronic pressure overload, via suppressing Ang II-PKCβI-ERK1/2-regulated autophagy.

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          Most cited references24

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          p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload.

          Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function. However, prolonged cardiac hypertrophy causes heart failure, and its mechanisms are largely unknown. Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure. Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload. These results indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure.
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            Cardiac autophagy is a maladaptive response to hemodynamic stress.

            Cardiac hypertrophy is a major predictor of heart failure and a prevalent disorder with high mortality. Little is known, however, regarding mechanisms governing the transition from stable cardiac hypertrophy to decompensated heart failure. Here, we tested the role of autophagy, a conserved pathway mediating bulk degradation of long-lived proteins and cellular organelles that can lead to cell death. To quantify autophagic activity, we engineered a line of "autophagy reporter" mice and confirmed that cardiomyocyte autophagy can be induced by short-term nutrient deprivation in vivo. Pressure overload induced by aortic banding induced heart failure and greatly increased cardiac autophagy. Load-induced autophagic activity peaked at 48 hours and remained significantly elevated for at least 3 weeks. In addition, autophagic activity was not spatially homogeneous but rather was seen at particularly high levels in basal septum. Heterozygous disruption of the gene coding for Beclin 1, a protein required for early autophagosome formation, decreased cardiomyocyte autophagy and diminished pathological remodeling induced by severe pressure stress. Conversely, Beclin 1 overexpression heightened autophagic activity and accentuated pathological remodeling. Taken together, these findings implicate autophagy in the pathogenesis of load-induced heart failure and suggest it may be a target for novel therapeutic intervention.
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              Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II.

              The angiotensin II type 1 (AT1) receptor has a crucial role in load-induced cardiac hypertrophy. Here we show that the AT1 receptor can be activated by mechanical stress through an angiotensin-II-independent mechanism. Without the involvement of angiotensin II, mechanical stress not only activates extracellular-signal-regulated kinases and increases phosphoinositide production in vitro, but also induces cardiac hypertrophy in vivo. Mechanical stretch induces association of the AT1 receptor with Janus kinase 2, and translocation of G proteins into the cytosol. All of these events are inhibited by the AT1 receptor blocker candesartan. Thus, mechanical stress activates AT1 receptor independently of angiotensin II, and this activation can be inhibited by an inverse agonist of the AT1 receptor.
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                Author and article information

                Journal
                Acta Pharmacol Sin
                Acta Pharmacol. Sin
                Acta Pharmacologica Sinica
                Nature Publishing Group
                1671-4083
                1745-7254
                August 2014
                07 July 2014
                : 35
                : 8
                : 1005-1014
                Affiliations
                [1 ]Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University , Shanghai 200032, China
                [2 ]Sir Run Run SHAW Hospital, Zhejiang University , Hangzhou 310016, China
                Author notes
                [#]

                These authors contributed equally to this manuscript.

                Article
                aps201445
                10.1038/aps.2014.45
                4125714
                24998254
                9f14bdc0-1e77-478b-9fe7-64c84fb4edf9
                Copyright © 2014 CPS and SIMM
                History
                : 09 December 2013
                : 04 May 2014
                Categories
                Original Article

                Pharmacology & Pharmaceutical medicine
                aliskiren,renin,cardiac hypertrophy,pressure overload,autophagy,angiotensin ii,pkc,erk1/2,3-methyladenine,ly333531,cardiomyocyte

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