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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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Related in: MedlinePlus

(G) Representative gel blots and quantitative analysis of pPKCβI, pERK1/2, LC3-II, and Beclin-1. n=6. Mean±SEM. bP<0.05 vs Sham. eP<0.05 vs TAC. hP<0.05 vs LY. LY, LY333531 (a PKCβI inhibitor, 1 mg·kg−1·d−1, po).
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fig5G: (G) Representative gel blots and quantitative analysis of pPKCβI, pERK1/2, LC3-II, and Beclin-1. n=6. Mean±SEM. bP<0.05 vs Sham. eP<0.05 vs TAC. hP<0.05 vs LY. LY, LY333531 (a PKCβI inhibitor, 1 mg·kg−1·d−1, po).

Mentions: To confirm the relationship among PKCβI, ERK1/2, and autophagy in vivo, a PKCβI inhibitor, LY333531 (LY), was employed. Echocardiographic and histological analysis showed that LY effectively inhibited cardiac hypertrophy, fibrosis and dysfunction induced by TAC without lowering ABP and LVESP (Figure S3, S4). Further electron microscopic analysis showed that the number of autophagic structures decreased significantly following LY administration when compared with the amount of structures noted in the TAC control group (Figure 5D, 5E), and the same results were observed in the corresponding mRNA expression levels of autophagy-related markers Atg5 and Atg16 L1 (Figure 5F). Moreover, Western blot results demonstrated that LY also clearly abrogated the elevations in pERK1/2, LC3-II, and Beclin-1 induced by TAC (Figure 5G). Taken together, our results consistently demonstrated the close relationship among PKCβI, ERK1/2, and autophagy.


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)

(G) Representative gel blots and quantitative analysis of pPKCβI, pERK1/2, LC3-II, and Beclin-1. n=6. Mean±SEM. bP<0.05 vs Sham. eP<0.05 vs TAC. hP<0.05 vs LY. LY, LY333531 (a PKCβI inhibitor, 1 mg·kg−1·d−1, po).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4125714&req=5

fig5G: (G) Representative gel blots and quantitative analysis of pPKCβI, pERK1/2, LC3-II, and Beclin-1. n=6. Mean±SEM. bP<0.05 vs Sham. eP<0.05 vs TAC. hP<0.05 vs LY. LY, LY333531 (a PKCβI inhibitor, 1 mg·kg−1·d−1, po).
Mentions: To confirm the relationship among PKCβI, ERK1/2, and autophagy in vivo, a PKCβI inhibitor, LY333531 (LY), was employed. Echocardiographic and histological analysis showed that LY effectively inhibited cardiac hypertrophy, fibrosis and dysfunction induced by TAC without lowering ABP and LVESP (Figure S3, S4). Further electron microscopic analysis showed that the number of autophagic structures decreased significantly following LY administration when compared with the amount of structures noted in the TAC control group (Figure 5D, 5E), and the same results were observed in the corresponding mRNA expression levels of autophagy-related markers Atg5 and Atg16 L1 (Figure 5F). Moreover, Western blot results demonstrated that LY also clearly abrogated the elevations in pERK1/2, LC3-II, and Beclin-1 induced by TAC (Figure 5G). Taken together, our results consistently demonstrated the close relationship among PKCβI, ERK1/2, and autophagy.

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