Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 6  |  Issue : 2  |  Page : 92-101

Deciphering the role of autophagy in heart failure


1 Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, USA; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
2 Public Health Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland; Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
3 University of Liverpool Institute of Ageing and Chronic Disease, Liverpool Centre for Cardiovascular Science, Liverpool, UK
4 Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, USA

Date of Submission07-May-2021
Date of Acceptance07-Jun-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Daniel J Klionsky
Department of Molecular, Cellular and Developmental Biology, Life Sciences Institute, University of Michigan, Ann Arbor
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2470-7511.320324

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  Abstract 


Heart failure (HF) refers to a progressive pathological condition when cardiac muscles fail to pump adequate blood supply (cardiac output) to meet the metabolic demand of the body. Among various cellular and molecular mechanisms identified for the onset and progression of HF, autophagy dysregulation is increasingly getting recognized. Autophagy is a natural cellular process that is observed in almost all eukaryotic cells. Autophagy removes damaged/long-lived organelles, protein aggregates, and unwanted cellular compomemts via forming autophagosomes then fusing with lysosomes. Although mild-to-moderate induction of autophagy is deemed cytoprotective and adaptive, excessive or unchecked induction of autophagy can be detrimental and maladaptive. Both adaptive and maladaptive autophagy play a vital role in the pathophysiology of HF. In the current review, we provide an overview of autophagy regulation in HF and possible strategies targeting autophagy for the management of HF.

Keywords: Autophagy; Cardiac myocytes; Heart failure; Stress; Therapeutics


How to cite this article:
Ajoolabady A, Tuomilehto J, H. Lip GY, Klionsky DJ, Ren J. Deciphering the role of autophagy in heart failure. Cardiol Plus 2021;6:92-101

How to cite this URL:
Ajoolabady A, Tuomilehto J, H. Lip GY, Klionsky DJ, Ren J. Deciphering the role of autophagy in heart failure. Cardiol Plus [serial online] 2021 [cited 2021 Nov 27];6:92-101. Available from: https://www.cardiologyplus.org/text.asp?2021/6/2/92/320324




  Introduction Top


Macroautophagy is the major type of autophagy present in almost all eukaryotic cells. Macroautophagy (from now on referred to as autophagy) denotes a process that recognizes, sequesters and degrades intracellular components including damaged/long-lived organelles, pathogens, and protein/lipid aggregates.[1],[2],[3],[4] In mammalian cells, autophagy is activated in response to multiple stress conditions, including metabolic stress and energy crisis, oxidative stress, invasion of pathogens, ischemia and reperfusion, physical trauma, and inflammation.[5],[6],[7],[8] Indeed, autophagy helps maintain cellular homeostasis by removing superfluous materials and recycling energy-generating elements such as amino acids and glucose.[9],[10],[11],[12] In this context, autophagy is a cytoprotective mechanism and is termed “adaptive/mild/cytoprotective” autophagy. However, ample evidence has shown that hyperactivation of autophagy can be detrimental and may lead to autophagy-dependent cell death (autosis) independent of other forms of cell death such as apoptosis, ferroptosis, and necroptosis. Therefore, hyperactivated autophagy is termed “maladaptive/excessive/unchecked autophagy.”[13],[14],[15],[d16]

Mechanistically, the autophagy process is initiated with the formation of a temporary double-membrane compartment known as a phagophore. The phagophore is nucleated and surrounds the targeted cellular components, namely autophagy cargos. Subsequently, phagophores mature into another temporary double-membraned structures, namely autophagosomes, which transport the sequestered autophagy cargos before the fusion with lysosomes for ultimate degradation of the cargos content into new building blocks and ATP regeneration.[8],[15],[17],[18] Construction of autophagosomes is a rather complicated and highly regulated process that entails a protein family of autophagy-targeted genes (ATG). These ATGs are hierarchically recruited to phagophore formation site to mediate the formation of phagophores, and autophagosomes, and also participate in fusion with the lysosomes.[17],[18] While ATG proteins are primary constituents of the autophagy machinery, other proteins and complexes such as 5' AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin kinase complex 1 (MTORC1) also participate in the signaling regulation of autophagy process.[18] Among various environmental factors, oxidative stress, abiotic stress, pathogens, ischemia, starvation, and nutrient deprivation are well-known inducers for autophagy in the mammalian cells.[15] To delineate the role of signaling pathways in the regulation of autophagy, we put cardiomyocytes under the perspective of consistent energy crisis such as glucose deprivation (GD) and amino acid deprivation (AAD) [Figure 1]. GD significantly reduces adenosine monophosphate (AMP) level in the cytosol and thereby activates AMPK. Being a master upstream regulator of autophagy, AMPK phosphorylates/activates other autophagy regulators including mitogen-activated protein kinase 8, forkhead box O transcription factor family, sirtuin 1, and tumor protein p53, all of which translocate to the nucleus and regulate ATG and autophagy-associated genes.[1],[2],[19],[20],[21] AMPK also activates other proteins such as regulatory-associated protein of MTOR complex 1 and TSC complex subunit 1/2 which regulate/inhibit MTORC1 and activate unc-51 like autophagy activating kinase 1 (ULK1). Subsequently, ULK1 initiates autophagy by forming the ULK1-autophagy-related 13 (ATG13)-ATG101-RB1-inducible coiled-coil 1 complex (also known as the autophagy initiation complex). In the next step, Class III phosphatidylinositol 3-kinase complex that contains phosphatidylinositol 3-kinase catalytic subunit type 3, phosphoinositide-3-kinase regulatory subunit 4, ATG14, and beclin 1 (BECN1) mediates the formation of phagophores. Ultimately, two conjugation systems similar to ubiquitin build protein complexes ATG5-ATG12-autophagy-related 16-like 1 and autophagy related 8-phosphatidylethanolamine that orchestrate the size and construction of autophagosomes around autophagy cargo that is supposed to be encapsulated within autophagosomes. Fusion between autophagosome and lysosome confers degradation of autophagy cargo into its building blocks[1],[2],[19],[20],[21] [Figure 1]. Due to the cardinal and indispensable role of autophagy in the maintenance of cellular homeostasis and alleviation of cellular stress, autophagy process is implicated in a variety of human diseases such as cancer,[22],[23],[24] neurodegenerative, cardiovascular, and metabolic diseases, as well as heart failure (HF).[1],[2],[3] In the current review, we provide an overview on the role of autophagy in the etiology of HF and explain the rationale for targeting autophagy as a new therapeutic strategy in the management of HF.
Figure 1: Autophagy machinery and its potential regulators.
Energy crises such as GD and AAD can activate upstream signaling pathways of autophagy. GD culminates in AMP reduction in the cytosol, which subsequently activates AMPK. AMPK is a master regulator of autophagy and phosphorylates/activates other autophagy regulator proteins such as MAPK8, FOXOs, SIRT1, and TP53, all of which, translocate to the nucleus and regulate autophagy-associated genes. Besides, AMPK mediates MTORC1 inhibition, which results in ULK1 activation. The ULK1 complex initiates autophagy in association with ATG proteins that result in the formation of the phagophore, the autophagosome, and ultimately the autolysosome. If this process continues excessively it can lead to maladaptive autophagy, however, its basal induction is an adaptive response to GD and AAD and other stress types.[1],[2],[19],[20],[21] GD: Glucose deprivation, AAD: Amino acid deprivation, AMPK: AMP-activated protein kinase,CAMKK2: Calcium/calmodulin dependent protein kinase kinase 2,CALM1: Calmodulin 1, MAPK8: Mitogen-activated protein kinase 8, ULK1: Unc-51 like autophagy activating kinase 1, FOXO: Forkhead box O transcription factor family, BCL2: BCL2 apoptosis regulator, DAPK1: Death associated protein kinase 1, DDIT4: DNA damage-inducible transcript 4, GABARAPL1: GABA type A receptor-associated protein like 1, JUN: Jun proto-oncogene, AP-1 transcription factor subunit, SIRT1: Sirtuin 1, TP53: Tumor protein p53, MTORC1: Mechanistic target of rapamycin kinase complex 1, ATG: autophagy-targeted genes, DRAM1: DNA damage-regulated autophagy modulator 1, BNIP3: BCL2 interacting protein 3, AMBRA1: Autophagy and beclin 1 regulator 1, FUNDC1: FUN14 domain containing 1


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  Pathogenesis of Heart Failure Top


HF is a persistent and progressive condition, in which the cardiac muscle fails to pump adequate blood supply to the body to meet the metabolic demand for oxygen and nutrients. Ample evidence to date has indicated that HF pathogenesis is an array of complex cellular and molecular alterations that ultimately culminate in cardiomyocyte death.[25],[26],[27],[28],[29] HF is derived from health conditions that impair the heart or dampen its normal function. A myriad of lifestyle factors such as cigarette smoking, consumption of a high fat diet, being overweight, and a sedentary life style can all predispose to the etiology of HF.[30],[31] Coronary artery disease is a condition that can contribute to HF. Ensuring the formation of fatty and cholesterol deposits in myocardial vessles, cardiac blood perfusion is gradually diminished due to inadequate blood flow and increased vascular resistance, en route to HF over time.[32] Myocardial infarction is an another contributing factor of HF and occurs when an artery gets obstructed and fails to carry blood to cardiac muscles. As a result, part of myocardium suffers from cell death and is unable to contract sufficiently and pump blood adequately.[33] Further, uncorrected high blood pressure is another serious factor which promotes HF. With the higher blood pressure (afterload), cardiac muscle is forced to pump harder, resulting in weaker and larger ventricular chambers over time.[34] Heart valve derangements may also contribute to the malfunction of cardiac pump. When valves fail to open and close properly, cardiac muscle is forced to pump harder, again resulting in HF.[35] The association of HF with other organs is also complex with more and more physicians and researchers perceiving HF as a multiorgan disease.[36] For instance, some evidence suggests that a damaged bowel wall allows the escape of bacterial endotoxins, which may provoke activation of proinflammatory cytokines in the setting of chronic HF.[36] Hypertension also contributes to the emergence of HF syndrome. Hypertrophy evoked by pressure overloaded in left ventricle (LV) results in ventricular diastolic impairment, myocardial infarction, and LV systolic dysfunction.[37],[38] Examining T-cell recruitment to LV demonstrates that T-cell activation along with endothelial activation culminates in T-cell infiltration that contributes to HF. Mechanistically, T-cell infiltration activates cytokine release and triggers fibrotic cell death and hypertrophy.[39] Given that cardiomyocytes are prone to infection, inflammatory responses are mounted in these cells following infection via the generation of pro-inflammatory cytokines and the function of natural killer cells and monocytes, which provoke apoptosis.[40],[41] Therefore, inflammation also plays a role in the pathogenesis of HF.

Besides, genome-wide association studies reveal 12 variants at 11 genomic loci associated with LV dysfunction, atrial fibrillation, and HF, suggesting that HF can be categorized as a rather complex genetic disease.[42] Moreover, Qishenkeli, a traditional Chinese medicine, attenuates reactive oxygen species generation, improves mitochondrial integrity, and inhibits apoptosis, and with specific regard to the cardiovascular system reduces infarct size and fibrosis and improves cardiac function.[43] Thus, apoptosis and fibrosis are two common culprit cellular processes, contributing to HF. In line with this, there is a plethora of evidence that autophagy also takes part in the pathology of HF, and modulation of autophagy could be a potential area for the management of HF.[27] Baseline autophagy induction acts as a protective and housekeeping mechanism that sustains ventricular mass and cardiomyocyte function.[44],[45] Upregulation of autophagy has been reported in failing heart in animal models with a protective function; however, in load-induced HF, excessive autophagy may contribute to cell death of cardiomyocytes and further exacerbation of HF.[45],[46] Thus, dysfunction of basic autophagy may predispose to the onset of HF, while excessive or maladaptive autophagy may contribute to the worsening of HF, in a manner reminiscent of apoptosis and fibrosis. In the section below, we briefly describe both protective and detrimental role of autophagy in HF.


  Autophagy in Heart Failure Top


Various experimental findings have favored a protective role for adaptive autophagy in the pathogenesis of HF, whereas maladaptive autophagy may provoke HF.[45] Adaptive autophagy is often reported to be defective upon HF, whereas maladaptive autophagy is commonly observed during disease progression. For example, Oka et al. determined that failure of autophagy in capturing mitochondrial DNA and its subsequent degradation in deoxyribonuclease 2, lysosomal-deficient hearts can result in Toll-like receptor (TLR) 9-mediated inflammation in cardiomyocytes, resulting in dilated cardiomyopathy and myocarditis.[47] These findings favor a notion of defective autophagy in HF etiology. In a murine model of postinfarction HF, induction of mild autophagy using either chemical inducers or caloric restriction attenuates infarct size and alleviates cardiac dysfunction during chronic postinfarct stages, suggesting a protective role for adaptive autophagy in HF-induced myocardial damage.[48] Besides, LV tissue samples from dilated cardiomyopathy patients displayed changes in the levels of autophagy-associated genes including calcium-binding and coiled-coil domain 2 and nuclear receptor-binding protein 2 in close association with cardiac remodeling and dysfunction.[49] This study suggests that adaptive autophagy becomes defective to evoke LV dysfunction, possibly due to changes in genetic modulation of autophagy under HF. Moreover, autophagy genes along with endoplasmic reticulum (ER) stress-associated genes are upregulated in a mouse model of HF with arrhythmias.[10],[50] Indeed, adaptive autophagy tends to reverse ER stress, a maladaptive process in HF.

Mitophagy is a selective type of autophagy that removes damaged/long-lived mitochondria and plays a crucial role in mitochondrial quality and integrity in cardiomyocytes.[1],[51] Shirakabe et al. subjected mice to transverse aortic constriction as a model of cardiac hypertrophy and found transiently upregulated mitophagy followed by subsequent downregulation of mitophagy. In addition, these investigators showed that mitophagy downregulation culminates in mitochondrial impairment and HF. However, reactivation of mitophagy alleviates HF upon pressure overload challenge.[52] Hence, strategies to reinvigorate adaptive mitophagy may be of promise in diseased cardiomyocytes upon HF challenge.

Ferritinophagy is a form of selective autophagy that degrades ferritin to release Fe2+ into the cytosol and may lead to ferroptotic cell death via cytosolic accumulation of Fe2+.[53],[54] In line with this, the activation of ferritinophagy can lead to HF development, whereas its inhibition prevents HF in a pressure overload-induced mouse model of dilated cardiomyopathy.[55] Therefore, certain types of autophagy such as ferritinophagy and mitophagy are adaptive responses that undergo mild induction during HF.

Although basal autophagy is generally cytoprotective, excessive autophagy can exacerbate HF pathology. For example, lymphocyte antigen 86 (Ly86) deletion hyperactivates autophagy by triggering ROS-MAPK signaling cascade, en route to the progression of murine HF with preserved ejection fraction (HFpEF).[56] Thus, modulation of LY86 may be a potential strategy to maintain basal autophagy in the face of HF. Moreover, activation of AMPK attenuates excessive autophagy via the modulation of MTORC2 and its downstream signaling, which prevents HF and alleviates cardiac dysfunction, suggesting a dual role of AMPK in autophagy regulation.[57] In addition, excessive autophagy culminates in necroptotic cell death in end-stage HF, but the receptor interacting serine/threonine kinase 1-nuclear factor kappa B subunit 1 axis counters cell death and is correlated with cell survival.[58] Further, TLR3 upregulation induces Toll-like receptor adaptor molecule 1 signaling, which culminates in excessive autophagy in murine chronic myocardial infarction models.[59] However, Tlr3 knockout effectively interrupts autophagy, diminishes infarct size, and alleviates HF severity. Therefore, TLR3 upregulation contributes to excessive autophagy ensuing in myocardial infarction, which favors HF.

Of note, vagus nerve stimulation (VNS) is a newly identified therapy for chronic systolic HF. Upon VNS challenge, microRNA MIR183-3p significantly downregulates BCL2-interacting protein 3 like (BNIP3L) and inhibits BNIP3L-mediated autophagy. Therefore, the upregulation of MIR183-3p, which occurs during VNS, is a potential strategy to reduce excessive autophagy and confer cardioprotection.[60] Along these lines, angiotensin converting enzyme 2 administration inhibits the damaging role of doxorubicin and remarkably alleviates LV contractility dysfunction, which is attributed to the upregulation of microRNA Mir30e that targets the three prime untranslated region of BECN1 and inhibits its expression.[61] Thus, microRNA Mir30e confers cardioprotection via the inhibition of excessive autophagy.

One may ask what is the difference between adaptive and maladaptive autophagy in terms of mechanism, inducing factors, and regulatory proteins. The current literature suggests that adaptive and maladaptive autophagy are favored with the same regulatory proteins, pathways, and mechanisms, as well as inducing factors, except the extent and duration of their induction. Mild induction of autophagy confers adaptive function in cardiomyocytes, while persistent induction of autophagy confers maladaptive functions and activates cell death domains.[62] Nonetheless, the fine-line separately adapative and maladaptive autophagy remains essentially unclear. Besides, the threshold at which mild induction converts to excessive or persistent induction differs in different cell types and organs. Further, determination of this threshold is still a challenge, and we propose the application of mathematical and statistical analysis to determine the persistance and endurance of induction at which adaptive autophagy ultimately turns to maladaptive autophagy. Taken together, both adaptive and maladaptive autophagy are reported in HF. Thus, it can be perceived that the application of strategies to maintain adaptive autophagy, while suppressing maladaptive autophagy should be practiced for clinical management of HF.


  Autophagy Modulation for the Management of Heart Failure Top


A number of maneuvers have been considered for the manipulation of autophagy in HF. The very first step in targeting autophagy is perhaps to recognize molecules governing autophagy alteration in HF. For example, eva-1 homolog A, regulator of programmed cell death (EVA1A) is an ER- and lysosome-associated protein that maintains cardiac homeostasis. Interestingly, cardiac-specific knockout of Eva1a results in autophagy inhibition and apoptosis activation in mice. The underlying mechanism is that eva1a-knockout induces MTORC1 activation, which suppresses autophagy, leading to sarcomere disorganization, mitochondrial damage, reduced ATP production, and development of HF.[63] This study further indicates a promising role of autophagy in the prevention of HF. Besides, EVA1A can be a potential therapeutic target to sustain cytoprotective autophagy in cardiomyocytes in the realm of HF. Subjecting FYVE and coiled-coil domain autophagy adaptor 1 (FYCO1)-deficient mice to pressure overload and starvation impairs autophagy and cardiac function. However, FYCO1 overexpression reactivates autophagy to boost cardiomyocyte resistance against pathological biomechanical stress.[64] This observation shows that FYCO1 is also a potential therapeutic target for autophagy modulation upon HF challenge. Moreover, mitochondrial calcium uniporter (FYCO1) inhibition upregulates parkin RBR E3 ubiquitin protein ligase and PTEN-induced kinase 1, sustains mitochondrial integrity, downregulates SQSTM1, and promotes microtubule-associated protein 1 light chain 3 beta, to evoke protection in both early and end stage of pressure overload-induced HF. Therefore, MCU inhibition activates mitophagy and autophagy and may be considered a new therapeutic target for the manipulation of autophagy upon HF.[65]

Besides specific therapeutic targets for the manipulation of autophagy, there are general strategies to modulate autophagy in the mammalian cells.[22],[23],[24],[66],[67],[68] These strategies are based on using therapeutic compounds to target core autophagy proteins or their upstream signaling pathways. [Figure 2] summarizes these compounds and their targets.[69] In addition, [Table 1] lists newly identified compounds that are under preclinical and clinical research that can be used for autophagy modulation upon HF.[70],[71],[72],[73],[74],[75],[76],[77]
Table 1: Autophagy-modulating compounds in the cardiovascular system.

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Figure 2: Autophagy modulators for the management of heart failure.
The natural compounds shown in the figure are potential activators of adaptive autophagy and suppressors of maladaptive autophagy that have been examined in animal studies of human diseases. Natural autophagy inducers manipulate different regulatory proteins that culminate in autophagy initiation and activation. However, natural maladaptive autophagy suppressors have been reported to block excessive induction of autophagy in mammalian cells. Even though the endurance and severity of the induction that convert adaptive autophagy to maladaptive autophagy are still unmeasurable, maladaptive autophagy suppressors might be useful to suppress maladaptive autophagy upon advanced stages of HF.[1,69] SIRT3: Sirtuin 3, MAPK1/3: Mitogen-activated protein kinase 1/3, BNIP3: BCL2-interacting protein 3, RAB7: Member RAS oncogene family, VDAC1: Voltage-dependent anion channel 1, FOXO3A: Forkhead box O3a, AKT1: AKT serine/threonine kinase 1, MXYF: Mu-Xiang-You-Fang [Chinese herbal compound], TSG: Tetrahydroxystilbene glucoside derived from Fallopia multiflora


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  Concluding Remarks Top


In sum, autophagy functions as a double-edged sword in the pathology of HF. On the one hand, adaptive autophagy prevents HF or alleviates HF symptoms. On the other hand, maladaptive autophagy is one of the underlying causes of HF pathology. Therefore, it is plausible to conclude that intervention which halts excessive induction of autophagy or maintains adaptive autophagy should be engaged in the clinical management of HF. Further studies are required to identify new therapeutic targets capable of manipulating autophagy or selective autophagy such as mitophagy in the management of HF. In particular, application of common pharmaceutical and natural compounds to manipulate autophagy may be recommended in the prevention or treatment of HF.

Financial support and sponsorship

This study is supported by the funds from the Science and Technology Commission of Shanghai Municipality (No. 18411950200).

Conflicts of interest

Jun Ren is an Editorial Board member of Cardiology Plus. The article was subject to the journal's standard procedures, with peer review handled independently of these Editorial Board members and their research groups.



 
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