Up-regulating autophagy by targeting the mTOR-4EBP1 pathway: a possible mechanism for improving cardiac function in mice with experimental dilated cardiomyopathy

Bo Jin,Quzhen Geshang,Bangwei Wu,Haiming Shi,Jun Zhu

doi:10.1186/s12872-020-01365-9

Bo Jin, Quzhen Geshang + Show 3 more

Open Access

https://doi.org/10.1186/s12872-020-01365-9

Copy DOI

Abstract

BackgroundAutophagy plays a crucial role in the pathological process of cardiovascular diseases. However, little is known about the pathological mechanism underlying autophagy regulation in dilated cardiomyopathy (DCM).MethodsWe explored whether up-regulating autophagy could improve cardiac function in mice with experimental DCM through the mTOR-4EBP1 pathway. Animal model of DCM was established in BALB/c mice by immunization with porcine cardiac myosin. Both up- or down-regulation of autophagy were studied by administration of rapamycin or 3-MA in parallel. Morphology, Western blotting, and echocardiography were applied to confirm the pathological mechanisms.ResultsAutophagy was activated and autophagosomes were significantly increased in the rapamycin group. The collagen volume fraction (CVF) was decreased in the rapamycin group compared with the DCM group (9.21 ± 0.82% vs 14.38 ± 1.24%, P < 0.01). The expression of p-mTOR and p-4EBP1 were significantly decreased in rapamycin-induced autophagy activation, while the levels were increased by down-regulating autophagy with 3-MA. In the rapamycin group, the LVEF and FS were significantly increased compared with the DCM group (54.12 ± 6.48% vs 45.29 ± 6.68%, P < 0.01; 26.89 ± 4.04% vs 22.17 ± 2.82%, P < 0.05). As the inhibitor of autophagy, 3-MA aggravated the progress of maladaptive cardiac remodeling and declined cardiac function in DCM mice.ConclusionsThe study indicated a possible mechanism for improving cardiac function in mice with experimental DCM by up-regulating autophagy via the mTOR-4EBP1 pathway, which could be a promising therapeutic strategy for DCM.

Highlights

Autophagy plays a crucial role in the pathological process of cardiovascular diseases
General characteristics The animal model was successfully established in male BALB/c mice, and twenty-four dilated cardiomyopathy (DCM) mice were randomly divided into DCM group, rapamycin group, and 3-MA group
No significant difference was found in the body weight, heart weight and heart weight/body weight (HW/BW), a tendency was found that the body weight was slightly decreased in the 3-MA group, it did not reach the statistically significant level (Table 1)

Summary

Introduction

Autophagy plays a crucial role in the pathological process of cardiovascular diseases. Little is known about the pathological mechanism underlying autophagy regulation in dilated cardiomyopathy (DCM). Dilated cardiomyopathy (DCM) is one of the most common cardiomyopathy worldwide characterized by left ventricular dilation and decline in contraction function, which is the third leading cause of congestive heart failure [1,2,3]. Recent studies of pathological mechanisms underlying heart failure focus on structural changes in Cardiovascular diseases including hypertrophic and ischemic cardiomyopathies are increasingly being reported to accumulate misfolded proteins and damaged organelles. As the highly conserved pathway, autophagy plays a crucial role in the pathological process of cardiovascular diseases. Little is known about the pathological mechanism underlying autophagy regulation by pharmacological interventions in dilated cardiomyopathy. We focuses on whether regulating autophagy could improve cardiac function in DCM mice through the mTOR-4EBP1 pathway

Methods

Results

Discussion

Conclusion