Effect of Autophagic Flux Impairment-mediated Apoptosis on Pressure Overload-induced Heart Failure

Shuangxiu LI; Qi ZHENG; Gaosheng YIN; Ping YANG; Lu LING

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Shuangxiu LI, Qi ZHENG, Gaosheng YIN, Ping YANG, Lu LING. Effect of Autophagic Flux Impairment-mediated Apoptosis on Pressure Overload-induced Heart Failure[J]. Journal of Kunming Medical University.

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Shuangxiu LI, Qi ZHENG, Gaosheng YIN, Ping YANG, Lu LING. Effect of Autophagic Flux Impairment-mediated Apoptosis on Pressure Overload-induced Heart Failure[J]. Journal of Kunming Medical University.

Shuangxiu LI, Qi ZHENG, Gaosheng YIN, Ping YANG, Lu LING. Effect of Autophagic Flux Impairment-mediated Apoptosis on Pressure Overload-induced Heart Failure[J]. Journal of Kunming Medical University.

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Effect of Autophagic Flux Impairment-mediated Apoptosis on Pressure Overload-induced Heart Failure

1.
Department of Cardiology，The Second Affiliated Hospital of Kunming Medical University，Kunming Yunnan 650101
2.
Rehabilitation College，Kunming Medical University，Kunming Yunnan 650500，China

Received Date: 2025-04-24
Available Online: 2025-09-19

Abstract

Abstract

Objective To explore the effect of autophagy and apoptosis on heart failure （HF） induced by pressure overload. Methods In the animal experiment, twenty C57/BL6J mice （aged 8-12 weeks） underwent transverse aortic constriction （TAC） to duplicate the model of pressure overload-induced HF. The mice were randomly divided into sham group （only threading was performed without ligation） and surgery group （TAC group）. Four weeks after post-operation, echocardiography was used to assess cardiac function. Ratios of heart weight/body weight （HW/BW） and heart weight/tibia length （HW/TL） were calculated. Histopathological changes were assessed with Masson and WGA staining. Quantitative real-time PCR was used to quantify the mRNA levels of hypertrophy-related genes: ANP, BNP, and β-MHC. Western blot analysis was used to determine the expression of autophagy proteins （Beclin1, P62, LC3-II/I） and apoptosis proteins （BCL2, BAX, c-caspase-3）. In the cell experiment, H9C2 cells were induced with angiotensin II （Ang II） to serve as an in vitro HF model. The H9C2 cells were divided into control （PBS group）, Ang II group, PBS with chloroquine （PBS+CQ group）, and Ang II with chloroquine （Ang II+CQ group）. After modeling, western blotting was used to assay apoptosis protein expression （Beclin1, P62, LC3-II/I, BAX, BCL2, c-caspase-3）. Autophagy double-labeled lentivirus mRFP-eGFP-LC3 was used to detect autophagic flux. Results Compared with the control group, the TAC group enlarged mouse heart, significantly increased HW/BW and HW/TL values, and decreased ejection fraction （EF%） and shortened fraction （FS%）（P < 0.001）. Fibrosis and collagen deposition were aggravated, the cross-sectional area of cardiomyocytes increased（P < 0.001）, and the mRNA expression levels of myocardial hypertrophy markers ANP, BNP and β-MHC （P < 0.001）were significantly increased, suggesting the successful construction of an understress-induced heart failure model in vivo. Compared to the control group, there was an upregulation of autophagy-related proteins Beclin1, P62, LC3-II/I（P < 0.01） and apoptosis proteins BAX, c-caspase-3（P < 0.01）, while the expression of BCL-2（P < 0.001）protein was reduced. In the cell experiments, in the in vitro heart failure model group, the autophagosomes were significantly increased, but there was no significant change in autophagic lysosomes, and autophagic flux was impaired. After blocking the autophagy process with chloroquine （CQ）, the Ang II+CQ group showed further increased expression of the autophagic proteins Beclin 1, LC3-II/I, P62（P < 0.05）, and apoptosis proteins BAX and cleaved caspase-3（P < 0.01） compared to the Ang II group, and a further decrease in protein levels of BCL-2（P < 0.001）. Additionally, CQ led to a significant increase in the number of autophagosomes, but there was no significant change in autophagic lysosomes, and autophagic flux was impaired. Conclusion Both autophagy and apoptosis are activated in pressure overload-induced heart failure, and impaired autophagic flux exacerbates apoptosis in this model.
- Heart failure,
- Transverse aortic constriction,
- Autophagy,
- Apoptosis,
- Cardiac remodeling

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References(25)

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