Role of Autophagy in Proteostasis: Friend and Foe in Cardiac Diseases

Li, Jin; Zhang, Deli; Wiersma, Marit; Brundel, Bianca J. J. M.

doi:10.3390/cells7120279

Cited by 40 publications

(30 citation statements)

References 147 publications

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“…The underlying activation of autophagy could alleviate cardiac dysfunction and fibrosis induced by TAC or pressure overload. 4,9,[28][29][30] A multitude of epidemiological and experimental studies suggested that exercise contributed to physiological cardiac hypertrophy and attenuated pathological hypertrophy induced by various heart diseases, including myocardial infarction, heart failure, and cardiomyopathy. 31,32) Some further studies were conducted to illuminate the potential mechanism of exercise-induced cardioprotec-tion, and the results suggested that exercise prevented fibrosis, pro-inflammatory cytokines, oxidative stress, and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…In this aspect, plenty of evidence indicates that cardiac autophagy is an underlying element for preserving cardiac function and protecting heart over hypoxia and LVH-induced cardiac dysfunction. [2][3][4] Therefore, it may be reasonable to hypothesize that exercise exerts a novel cardioprotective role through the mediation of autophagy signaling in the heart. Recent studies have shown that autophagy is involved in exercise-induced cardioprotection due to the upregulation of autophagy in both acute and endurance exercise.…”

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confidence: 99%

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Role of Exercise on Alleviating Pressure Overload-Induced Left Ventricular Dysfunction and Remodeling <i>via</i> AMPK-Dependent Autophagy Activation

Gao

et al. 2020

Int. Heart J.

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Cardiac hypertrophy is one of the significant risk factors that result in maladaptive cardiac remodeling and heart failure, and exercise is known to exert cardioprotection. In this research, the cardioprotective function and exercise mechanisms were explored. The rats underwent transverse aortic constriction (TAC) or a sham operation. The rats that received TAC were randomly assigned to five groups: (1) rats subjected to a sham operation as control group (SC), (2) rats that underwent TAC group (TC), (3) TAC and moderate-intensity exercise group (TE), (4) TE plus 3-MA group (TEM), and (5) TE plus Compound C group (TEC). The heart function was measured via echocardiography. Histological analysis and relative protein testing were conducted to analyze collagen deposition and apoptosis. Furthermore, western blot was employed to measure the protein expression of relevant signaling pathways. Impaired cardiac function, interstitial fibrosis, enhanced apoptosis, and ER stress were observed in the TACinduced left ventricular hypertrophy. Exercise attenuated TAC-induced cardiac dysfunction, interstitial fibrosis, and ER stress-related apoptosis. In addition, exercise significantly improved autophagy and upregulated AMPK phosphorylation. Furthermore, AMPK inhibitor Compound C repressed the activation of AMPK, and autophagy inhibitor 3-methyladenine reversed exercise-induced autophagy. All of these abolished the protection of exercise against cardiac dysfunction and fibrosis induced by TAC. Our results indicated that 4 weeks of treadmill exercise could alleviate pressure overload-induced LV dysfunction and remodeling via an autophagy-dependent mechanism, which was induced by enhancing autophagy through the activation of AMPK.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Role of Exercise on Alleviating Pressure Overload-Induced Left Ventricular Dysfunction and Remodeling <i>via</i> AMPK-Dependent Autophagy Activation

Gao

et al. 2020

Int. Heart J.

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“…including the ubiquitin-proteasomal system (UPS) and autophagy [9]. In general, cellular stress, including stress caused by cardiac disease, activates multiple stress pathways, including the cytosolic heat shock response, the endoplasmic reticulum (ER) unfolded protein response (UPR ER ), and the mitochondrial UPR (UPR mt ) [10][11][12].…”

Section: Of 15mentioning

confidence: 99%

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Jin

Zhang

Brundel

et al. 2019

Cells

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Cardiac disease is still the leading cause of morbidity and mortality worldwide, despite some exciting and innovative improvements in clinical management. In particular, atrial fibrillation (AF) and heart failure show a steep increase in incidence and healthcare costs due to the ageing population. Although research revealed novel insights in pathways driving cardiac disease, the exact underlying mechanisms have not been uncovered so far. Emerging evidence indicates that derailed proteostasis (i.e., the homeostasis of protein expression, function and clearance) is a central component driving cardiac disease. Within proteostasis derailment, key roles for endoplasmic reticulum (ER) and mitochondrial stress have been uncovered. Here, we describe the concept of ER and mitochondrial stress and the role of interactions between the ER and mitochondria, discuss how imbalance in the interactions fuels cardiac ageing and cardiac disease (including AF), and finally assess the potential of drugs directed at conserving the interaction as an innovative therapeutic target to improve cardiac function. of 15including the ubiquitin-proteasomal system (UPS) and autophagy [9]. In general, cellular stress, including stress caused by cardiac disease, activates multiple stress pathways, including the cytosolic heat shock response, the endoplasmic reticulum (ER) unfolded protein response (UPR ER ), and the mitochondrial UPR (UPR mt ) [10][11][12].Within the PQC, the ER and mitochondria play a critical role in the regulation of protein homeostasis and the maintenance of normal cellular function. The ER is an essential organelle involved in protein synthesis, folding, and trafficking. As protein folding is an error-prone process, the PQC system of the ER is specialized in optimizing this process, thereby preserving cardiac protein quality and homeostasis [13]. As approximately 30% of the cardiomyocyte volume is comprised of mitochondria, the maintenance of a healthy and functional mitochondrial PQC system, which includes molecular chaperones (e.g., HSP60 and HSP10) and proteases (e.g., ClpP), is critical to conserve the energy balance and cardiomyocyte function. The PQC system in mitochondria activates, upon stress, protein folding assistance mechanisms and promotes clearance of misfolded proteins to preserve mitochondrial function [14,15].Thus, a healthy proteostasis in cardiomyocytes safeguards the proper contractile function in the heart. The ER and mitochondria are essential organelles for regulating protein homeostasis, thereby guaranteeing cardiomyocyte function and survival. Therefore, a deeper understanding of ER and mitochondrial function during health and cardiac disease is required to ultimately develop novel therapeutic strategies. Role of the ER in Cardiac HealthThe ER is an essential organelle supporting multiple cellular processes such as protein synthesis, protein folding, regulation of Ca 2+ homeostasis, and contribution to the generation of autophagosomes and peroxisomes [16]. The ER lumen constitutes of a specialized fol...

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“…mTORC1 is a serine/threonine kinase and negatively regulates autophagy. 20,43,44 AMPK is responsible for sensing energy and nutrients and positively promotes autophagy by inhibiting mTORC1 or by phosphorylating Ulk1 at serine 313 and 777 and dissociating Ulk1 from mTORC1. 19,45,46 In this study, we found that Flt3 activation remarkably reduced Ang II-induced elevation of AMPK phosphorylation and the decrease of mTORC1 phosphorylation, resulting in the inactivation of autophagy ( Figure 6A,B).…”

Section: F I G U R Ementioning

confidence: 99%

Activated FMS‐like tyrosine kinase 3 ameliorates angiotensin II‐induced cardiac remodelling

Liang

Zhan

et al. 2020

Acta Physiologica

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Aim FMS‐like receptor tyrosine kinase 3 (Flt3) has been reported to be increased in cardiomyocytes responding to ischaemic stress. This study was to determine whether Flt3 activation could ameliorate pressure overload‐induced heart hypertrophy and fibrosis, and to elucidate the mechanisms of action. Methods In vivo cardiac hypertrophy and remodelling experiments were conducted by infusing angiotensin II (Ang II) chronically in male C57BL/6 mice. Flt3‐specific ligand (FL) was administered intraperitoneally every two days (5 µg/mouse). In vitro experiments on hypertrophy, apoptosis and autophagy mechanism were performed in neonatal rat cardiomyocytes (NRCMs) and H9c2 cells with adenovirus vector‐mediated overexpression of Flt3. Results Our results demonstrated that following chronic Ang II infusion for 4 weeks, the mice exhibited heart hypertrophy, fibrosis, apoptosis and contractile dysfunction. Meanwhile, Ang II induced autophagic responses in mouse hearts, as evidenced by increased LC3 II and decreased P62 expression. These pathological alterations in Ang II‐treated mice were significantly ameliorated by Flt3 activation with FL administration. In NRCMs and Flt3‐overexpressed H9c2 cells, FL attenuated Ang II‐induced pathological autophagy and inactivated AMPK/mTORC1/FoxO3a signalling, thereby efficiently mitigating cell hypertrophy and apoptosis. Conversely, the AMPK activator metformin or the mTORC1 inhibitor rapamycin reversed the effects of FL on the alterations of autophagy, hypertrophy and apoptosis in cardiomyocytes induced by Ang II. Conclusion Flt3 activation ameliorates cardiac hypertrophy, fibrosis and contractile dysfunction in the mouse model of chronic pressure overload, most likely via suppressing AMPK/mTORC1/FoxO3a‐mediated autophagy. These results provide new evidence supporting Flt3 as a novel therapeutic target in maladaptive cardiac remodelling.

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Role of Autophagy in Proteostasis: Friend and Foe in Cardiac Diseases

Cited by 40 publications

References 147 publications

Role of Exercise on Alleviating Pressure Overload-Induced Left Ventricular Dysfunction and Remodeling <i>via</i> AMPK-Dependent Autophagy Activation

Role of Exercise on Alleviating Pressure Overload-Induced Left Ventricular Dysfunction and Remodeling <i>via</i> AMPK-Dependent Autophagy Activation

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Activated FMS‐like tyrosine kinase 3 ameliorates angiotensin II‐induced cardiac remodelling

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