Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Aug 1;313(2):H304-H319.
doi: 10.1152/ajpheart.00145.2017. Epub 2017 Jun 2.

Autophagy modulation: a potential therapeutic approach in cardiac hypertrophy

Xuejun Wang  1 , Taixing Cui  2
Affiliations
Review

Autophagy modulation: a potential therapeutic approach in cardiac hypertrophy

Xuejun Wang et al. Am J Physiol Heart Circ Physiol. .

Abstract

Autophagy is an evolutionarily conserved process used by the cell to degrade cytoplasmic contents for quality control, survival for temporal energy crisis, and catabolism and recycling. Rapidly increasing evidence has revealed an important pathogenic role of altered activity of the autophagosome-lysosome pathway (ALP) in cardiac hypertrophy and heart failure. Although an early study suggested that cardiac autophagy is increased and that this increase is maladaptive to the heart subject to pressure overload, more recent reports have overwhelmingly supported that myocardial ALP insufficiency results from chronic pressure overload and contributes to maladaptive cardiac remodeling and heart failure. This review examines multiple lines of preclinical evidence derived from recent studies regarding the role of autophagic dysfunction in pressure-overloaded hearts, attempts to reconcile the discrepancies, and proposes that resuming or improving ALP flux through coordinated enhancement of both the formation and the removal of autophagosomes would benefit the treatment of cardiac hypertrophy and heart failure resulting from chronic pressure overload.

Keywords: autophagy; cardiac hypertrophy; mechanistic target of rapamycin; pressure overload; transcription factor EB.

PubMed Disclaimer

Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the author(s).

Figures

Fig. 1.
Fig. 1.
Schematic illustration of three forms of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). In macroautophagy, a portion of the cytoplasm including organelles is sequestered by an autophagosome, which delivers its content to the lysosome by fusing with lysosomes to form autolysosomes. For microautophagy, a small portion of the cytoplasm is directly captured by the lysosome via invagination of the lysosomal membrane. In CMA, individual protein molecules with a KFERQ-like motif are first recognized by cytosolic heat shock cognate 71-kDa protein (HSC70) and cochaperones. They then are translocated into the lysosome through interactions with lysosome-associated membrane protein (LAMP)2A, an integral membrane protein of the lysosome.
Fig. 2.
Fig. 2.
Schematic model of conventional autophagosome formation on the endoplasmic reticulum (ER) and the participation of autophagic regulators in mammalian cells. The phagophore originates from a domain of the ER called the omegasome, which is characterized by the presence of the phosphatidylinositol 3-phosphate (PI3P)-binding protein double FYVE-domain-containing protein 1(DFCP1). Stimulation of the UNC51-like kinase (ULK) complex activates the class III phosphoinositide 3-kinase (PI3K) complex, which consists of the core structure [beclin-1, vacuolar protein sorting (VPS)15, and VPS34] and two regulators [ATG14L and activating molecule in beclin 1-regulated autophagy 1 (AMBRA1)], enabling it to be relocated from the cytoskeleton to the preautophagosomal structure by the ER-located transmembrane protein vacuole membrane protein 1 (VMP1) to induce the production of PI3P. PI3P promotes the recruitment of WD repeat domain phosphoinositide-interacting protein (WIPI) proteins upstream of the two ubiquitination-like conjugation systems that elongate and seal the autophagosomal membrane. The first conjugation system results in the formation of the ATG12-ATG5-ATG16L1 complex on phagophore membrane. This complex acts as an E3-like enzyme in the second conjugation system to induce the second complex, which generates the phosphatidylethanolamine (PE)-conjugated form of light chain (LC)3 (LC3-II) from LC3-I. ATG9 (the ATG9-ATG2-ATG18 complex), another factor essential for this event, cycles between endosomes, the Golgi, and the phagophore, possibly carrying lipid components for membrane expansion.
Fig. 3.
Fig. 3.
Integrated autophagic signaling pathways in mammalian cells. Environmental or internal inputs including growth factors, cytokines, amino acids, stress, oxygen, and energy status trigger complicated signaling cascades, which may converge on mechanistic target of rapamycin complex (mTORC)1 to regulate autophagy. mTORC1 also regulates a variety of other biological processes such as protein and lipid synthesis as well as metabolism. mTORC2 regulates survival and metabolism as well as the cytoskeleton through the phosphorylation of many AGC kinases, including Akt, serum- and glucocorticoid-regulated kinase 1, and PKC-α (see text for details and definitions of abbreviations).
Fig. 4.
Fig. 4.
Mechanism governing transcription factor EB (TFEB) nuclear translocation. Under normal nutrient-rich conditions, TFEB is phosphorylated by mTORC1 on the lysosomal surface and is retained in the cytoplasm by 14-3-3 proteins. During nutrient deprivation or lysosomal stress (e.g., starvation and physical exercise), mTORC1 is inactivated and no longer able to phosphorylate TFEB while Ca2+ is released from the lysosome through the MCOLN1 Ca2+ channel, resulting in local calcineurin (Cn) activation, which, in turn, dephosphorylates TFEB. Dephosphorylated TFEB loses its ability to bind 14-3-3 proteins and can freely translocate to the nucleus, where it activates the transcription of a network of genes that regulates the lysosomal/autophagic pathway. [Ca2+]c, cystolic Ca2+ concentration. [Adapted from Ballabio (3).]
Fig. 5.
Fig. 5.
Autophagy in pressure overload-induced cardiac hypertrophy and failure. The relationship between autophagy activity, cardiac remodeling, and dysfunction as well as the mediators of autophagy activation or impairment in pressure-overloaded hearts is shown. Autophagy activation refers to the enhancement of lysosome-mediated clearance of substrate-loaded autophagosomes. Autophagy insufficiency refers to absolute or relative insufficiency of the lysosome-mediated clearance of autophagosomes, which may be caused by a decrease in autophagosome synthesis, an inhibition or failure of autophagosome-lysosome fusion, or suppressed lysosome function. Genetically tested autophagy modulators are listed underneath each autophagic state. Drp1, dynamin-related protein 1.
Fig. 6.
Fig. 6.
Potential strategies for improving cardiac autophagosome-lysosome pathway flux to treat maladaptive cardiac hypertrophy and heart failure. O/E, overexpression; QC, quality control.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ammirati E, Contri R, Coppini R, Cecchi F, Frigerio M, Olivotto I. Pharmacological treatment of hypertrophic cardiomyopathy: current practice and novel perspectives. Eur J Heart Fail 18: 1106–1118, 2016. doi:10.1002/ejhf.541. - DOI - PubMed
    1. Ao X, Zou L, Wu Y. Regulation of autophagy by the Rab GTPase network. Cell Death Differ 21: 348–358, 2014. doi:10.1038/cdd.2013.187. - DOI - PMC - PubMed
    1. Ballabio A. The awesome lysosome. EMBO Mol Med 8: 73–76, 2016. doi:10.15252/emmm.201505966. - DOI - PMC - PubMed
    1. Bartlett JJ, Trivedi PC, Yeung P, Kienesberger PC, Pulinilkunnil T. Doxorubicin impairs cardiomyocyte viability by suppressing transcription factor EB expression and disrupting autophagy. Biochem J 473: 3769–3789, 2016. doi:10.1042/BCJ20160385. - DOI - PubMed
    1. Bhuiyan MS, Pattison JS, Osinska H, James J, Gulick J, McLendon PM, Hill JA, Sadoshima J, Robbins J. Enhanced autophagy ameliorates cardiac proteinopathy. J Clin Invest 123: 5284–5297, 2013. doi:10.1172/JCI70877. - DOI - PMC - PubMed

LinkOut - more resources