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

Weng LQ, Zhang WB, Ye Y, Yin PP, Yuan J, Wang XX, Kang L, Jiang SS, You JY, Wu J, Gong H, Ge JB, Zou YZ - Acta Pharmacol. Sin. (2014)

Bottom Line: The levels of signaling proteins were measured using Western blotting, while the expression of the relevant genes was analyzed using real-time QRT-PCR.These pathological alterations in TAC-mice were significantly ameliorated or blocked by ALK administration.In mechanically stretched cardiomyocytes, CGP53353 (a PKCβI inhibitor) prevented ERK phosphorylation and autophagic responses, while U0126 (an ERK inhibitor) blocked autophagic responses.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China.

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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Effect of 3-MA on TAC-induced cardiac hypertrophy, fibrosis and dysfunction. (A) Representative TEM images of left ventricular sections (scale bar: 500 nm, arrows indicating autophagic structures). (B) Echocardiographic parameter analysis. LVAWd, left ventricular anterior wall thickness at end-diastole; LVIDd, left ventricular internal dimension at end-diastole; LVFS, left ventricular fraction shortening; LVEF, left ventricular eject fraction. (C) Heart to body weight ratio (HW/BW). (D) Representative HE-stained left ventricular sections (scale bar: 20 μm) and quantitative analysis of cross-sectional area (CSA). (E) Representative Masson's trichrome-stained left ventricular sections (scale bar: 20 μm) and quantitative analysis of fibrotic area. Blue areas indicate fibrotic staining. n=6. Mean±SEM. bP<0.05 vs Sham. eP<0.05 vs TAC. hP<0.05 vs 3-MA. 3-MA, 3-methyladenine (autophagy inhibitor, 10 mg·kg−1 per week, ip).
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fig3: Effect of 3-MA on TAC-induced cardiac hypertrophy, fibrosis and dysfunction. (A) Representative TEM images of left ventricular sections (scale bar: 500 nm, arrows indicating autophagic structures). (B) Echocardiographic parameter analysis. LVAWd, left ventricular anterior wall thickness at end-diastole; LVIDd, left ventricular internal dimension at end-diastole; LVFS, left ventricular fraction shortening; LVEF, left ventricular eject fraction. (C) Heart to body weight ratio (HW/BW). (D) Representative HE-stained left ventricular sections (scale bar: 20 μm) and quantitative analysis of cross-sectional area (CSA). (E) Representative Masson's trichrome-stained left ventricular sections (scale bar: 20 μm) and quantitative analysis of fibrotic area. Blue areas indicate fibrotic staining. n=6. Mean±SEM. bP<0.05 vs Sham. eP<0.05 vs TAC. hP<0.05 vs 3-MA. 3-MA, 3-methyladenine (autophagy inhibitor, 10 mg·kg−1 per week, ip).

Mentions: To evaluate the role of autophagy in TAC-induced cardiac hypertrophy, fibrosis and dysfunction, Sham and TAC mice were treated with the autophagy inhibitor, 3-MA, for 4 weeks prior to the assessment of cardiac geometry and function. Our data revealed that 4 weeks of TAC without 3-MA treatment induced significant cardiac hypertrophy, fibrosis and dysfunction. Although 3-MA itself did not affect cardiac morphology or function at baseline, it notably attenuated TAC-induced cardiac hypertrophy, fibrosis and dysfunction, as evidenced by the overtly decreased LVAWd, HW/BW, CSA, and interstitial collagen volume, as well as the improved LVFS and LVEF (Figure 3), without lowering either ABP or LVESP (Figure S2). These data suggested a role for autophagy in TAC-induced cardiac hypertrophy, fibrosis and dysfunction.


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

Weng LQ, Zhang WB, Ye Y, Yin PP, Yuan J, Wang XX, Kang L, Jiang SS, You JY, Wu J, Gong H, Ge JB, Zou YZ - Acta Pharmacol. Sin. (2014)

Effect of 3-MA on TAC-induced cardiac hypertrophy, fibrosis and dysfunction. (A) Representative TEM images of left ventricular sections (scale bar: 500 nm, arrows indicating autophagic structures). (B) Echocardiographic parameter analysis. LVAWd, left ventricular anterior wall thickness at end-diastole; LVIDd, left ventricular internal dimension at end-diastole; LVFS, left ventricular fraction shortening; LVEF, left ventricular eject fraction. (C) Heart to body weight ratio (HW/BW). (D) Representative HE-stained left ventricular sections (scale bar: 20 μm) and quantitative analysis of cross-sectional area (CSA). (E) Representative Masson's trichrome-stained left ventricular sections (scale bar: 20 μm) and quantitative analysis of fibrotic area. Blue areas indicate fibrotic staining. n=6. Mean±SEM. bP<0.05 vs Sham. eP<0.05 vs TAC. hP<0.05 vs 3-MA. 3-MA, 3-methyladenine (autophagy inhibitor, 10 mg·kg−1 per week, ip).
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Related In: Results  -  Collection

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fig3: Effect of 3-MA on TAC-induced cardiac hypertrophy, fibrosis and dysfunction. (A) Representative TEM images of left ventricular sections (scale bar: 500 nm, arrows indicating autophagic structures). (B) Echocardiographic parameter analysis. LVAWd, left ventricular anterior wall thickness at end-diastole; LVIDd, left ventricular internal dimension at end-diastole; LVFS, left ventricular fraction shortening; LVEF, left ventricular eject fraction. (C) Heart to body weight ratio (HW/BW). (D) Representative HE-stained left ventricular sections (scale bar: 20 μm) and quantitative analysis of cross-sectional area (CSA). (E) Representative Masson's trichrome-stained left ventricular sections (scale bar: 20 μm) and quantitative analysis of fibrotic area. Blue areas indicate fibrotic staining. n=6. Mean±SEM. bP<0.05 vs Sham. eP<0.05 vs TAC. hP<0.05 vs 3-MA. 3-MA, 3-methyladenine (autophagy inhibitor, 10 mg·kg−1 per week, ip).
Mentions: To evaluate the role of autophagy in TAC-induced cardiac hypertrophy, fibrosis and dysfunction, Sham and TAC mice were treated with the autophagy inhibitor, 3-MA, for 4 weeks prior to the assessment of cardiac geometry and function. Our data revealed that 4 weeks of TAC without 3-MA treatment induced significant cardiac hypertrophy, fibrosis and dysfunction. Although 3-MA itself did not affect cardiac morphology or function at baseline, it notably attenuated TAC-induced cardiac hypertrophy, fibrosis and dysfunction, as evidenced by the overtly decreased LVAWd, HW/BW, CSA, and interstitial collagen volume, as well as the improved LVFS and LVEF (Figure 3), without lowering either ABP or LVESP (Figure S2). These data suggested a role for autophagy in TAC-induced cardiac hypertrophy, fibrosis and dysfunction.

Bottom Line: The levels of signaling proteins were measured using Western blotting, while the expression of the relevant genes was analyzed using real-time QRT-PCR.These pathological alterations in TAC-mice were significantly ameliorated or blocked by ALK administration.In mechanically stretched cardiomyocytes, CGP53353 (a PKCβI inhibitor) prevented ERK phosphorylation and autophagic responses, while U0126 (an ERK inhibitor) blocked autophagic responses.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institute of Biomedical Science, Fudan University, Shanghai 200032, China.

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.

Show MeSH
Related in: MedlinePlus