Top

Published in:

01-03-2011 | Riley Symposium

Is Autophagy in Response to Ischemia and Reperfusion Protective or Detrimental for the Heart?

Authors: Sebastiano Sciarretta, Nirmala Hariharan, Yoshiya Monden, Daniela Zablocki, Junichi Sadoshima

Published in: Pediatric Cardiology | Issue 3/2011

Abstract

Autophagy is a catabolic process that degrades long-lived proteins and damaged organelles by sequestering them into double membrane structures termed “autophagosomes” and fusing them with lysosomes. Autophagy is active in the heart at baseline and further stimulated under stress conditions including starvation, ischemia/reperfusion, and heart failure. It plays an adaptive role in the heart at baseline, thereby maintaining cardiac structure and function and inhibiting age-related cardiac abnormalities. Autophagy is activated by ischemia and nutrient starvation in the heart through Sirt1-FoxO- and adenosine monophosphate (AMP)-activated protein kinase (AMPK)-dependent mechanisms, respectively. Activation of autophagy during ischemia is essential for cell survival and maintenance of cardiac function. Autophagy is strongly activated in the heart during reperfusion after ischemia. Activation of autophagy during reperfusion could be either protective or detrimental, depending on the experimental model. However, strong induction of autophagy accompanied by robust upregulation of Beclin1 could cause autophagic cell death, thereby proving to be detrimental. This review provides an overview regarding both protective and detrimental functions of autophagy in the heart and discusses possible applications of current knowledge to the treatment of heart disease.

Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL, Habermann A, Griffiths G, Ktistakis NT (2008) Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol 182:685–701PubMedCrossRef

Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J, Mazure NM (2009) Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 29:2570–2581PubMedCrossRef

Decker RS, Wildenthal K (1980) Lysosomal alterations in hypoxic and reoxygenated hearts: I. Ultrastructural and cytochemical changes. Am J Pathol 98:425–444PubMed

Gottlieb RA, Carreira RS (2010) Autophagy in health and disease: 5. Mitophagy as a way of life. Am J Physiol Cell Physiol 299:C203–C210PubMedCrossRef

Gottlieb RA, Mentzer RM (2010) Autophagy during cardiac stress: joys and frustrations of autophagy. Annu Rev Physiol 72:45–59PubMedCrossRef

Gurusamy N, Lekli I, Gorbunov NV, Gherghiceanu M, Popescu LM, Das DK (2009) Cardioprotection by adaptation to ischaemia augments autophagy in association with BAG-1 protein. J Cell Mol Med 13:373–387PubMedCrossRef

Hamacher-Brady A, Brady NR, Gottlieb RA (2006) Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J Biol Chem 281:29776–29787PubMedCrossRef

Hariharan N, Maejima Y, Nakae J, Paik J, Depinho RA, Sadoshima J (2010) Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes. Circ Res 107(12):1470–1482PubMedCrossRef

Hariharan N, Zhai P, Sadoshima J (2010) Oxidative stress stimulates autophagic flux during ischemia/reperfusion. Antioxid Redox Signal (in press)

10.

He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93PubMedCrossRef

11.

Huang C, Yitzhaki S, Perry CN, Liu W, Giricz Z, Mentzer RM Jr, Gottlieb RA (2010) Autophagy induced by ischemic preconditioning is essential for cardioprotection. J Cardiovasc Transl Res 3:365–373PubMedCrossRef

12.

Kanamori H, Takemura G, Maruyama R, Goto K, Tsujimoto A, Ogino A, Li L, Kawamura I, Takeyama T, Kawaguchi T, Nagashima K, Fujiwara T, Fujiwara H, Seishima M, Minatoguchi S (2009) Functional significance and morphological characterization of starvation-induced autophagy in the adult heart. Am J Pathol 174:1705–1714PubMedCrossRef

13.

Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T, Mizushima N (2004) The role of autophagy during the early neonatal starvation period. Nature 432:1032–1036PubMedCrossRef

14.

Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477PubMedCrossRef

15.

Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42PubMedCrossRef

16.

Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, Levine B, Sadoshima J (2007) Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 100:914–922PubMedCrossRef

17.

Matsui Y, Kyoi S, Takagi H, Hsu CP, Hariharan N, Ago T, Vatner SF, Sadoshima J (2008) Molecular mechanisms and physiological significance of autophagy during myocardial ischemia and reperfusion. Autophagy 4:409–415PubMed

18.

Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, Maejima I, Shirahama-Noda K, Ichimura T, Isobe T, Akira S, Noda T, Yoshimori T (2009) Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 11:385–396PubMedCrossRef

19.

Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075PubMedCrossRef

20.

Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M, Omiya S, Mizote I, Matsumura Y, Asahi M, Nishida K, Hori M, Mizushima N, Otsu K (2007) The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 13:619–624PubMedCrossRef

21.

Nishida K, Yamaguchi O, Otsu K (2008) Crosstalk between autophagy and apoptosis in heart disease. Circ Res 103:343–351PubMedCrossRef

22.

Nishida K, Kyoi S, Yamaguchi O, Sadoshima J, Otsu K (2009) The role of autophagy in the heart. Cell Death Differ 16:31–38PubMedCrossRef

23.

Nishida Y, Arakawa S, Fujitani K, Yamaguchi H, Mizuta T, Kanaseki T, Komatsu M, Otsu K, Tsujimoto Y, Shimizu S (2009) Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461:654–658PubMedCrossRef

24.

Porrello ER, D’Amore A, Curl CL, Allen AM, Harrap SB, Thomas WG, Delbridge LM (2009) Angiotensin II type 2 receptor antagonizes angiotensin II type 1 receptor-mediated cardiomyocyte autophagy. Hypertension 53:1032–1040PubMedCrossRef

25.

Saftig P, Tanaka Y, Lullmann-Rauch R, von Figura K (2001) Disease model: LAMP-2 enlightens Danon disease. Trends Mol Med 7:37–39PubMedCrossRef

26.

Scherz-Shouval R, Elazar Z (2007) ROS, mitochondria, and the regulation of autophagy. Trends Cell Biol 17:422–427PubMedCrossRef

27.

Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z (2007) Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J 26:1749–1760PubMedCrossRef

28.

Takagi H, Matsui Y, Hirotani S, Sakoda H, Asano T, Sadoshima J (2007) AMPK mediates autophagy during myocardial ischemia in vivo. Autophagy 3:405–407PubMed

29.

Takemura G, Kanamori H, Goto K, Maruyama R, Tsujimoto A, Fujiwara H, Seishima M, Minatoguchi S (2009) Autophagy maintains cardiac function in the starved adult. Autophagy 5:1034–1036PubMedCrossRef

30.

Taneike M, Yamaguchi O, Nakai A, Hikoso S, Takeda T, Mizote I, Oka T, Tamai T, Oyabu J, Murakawa T, Nishida K, Shimizu T, Hori M, Komuro I, Shirasawa T, Mizushima N, Otsu K (2010) Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 6(5):600–606CrossRef

31.

Valentim L, Laurence KM, Townsend PA, Carroll CJ, Soond S, Scarabelli TM, Knight RA, Latchman DS, Stephanou A (2006) Urocortin inhibits Beclin1-mediated autophagic cell death in cardiac myocytes exposed to ischaemia/reperfusion injury. J Mol Cell Cardiol 40:846–852PubMedCrossRef

32.

Wang ZV, Rothermel BA, Hill JA (2010) Autophagy in hypertensive heart disease. J Biol Chem 285:8509–8514PubMedCrossRef

33.

Yan L, Vatner DE, Kim SJ, Ge H, Masurekar M, Massover WH, Yang G, Matsui Y, Sadoshima J, Vatner SF (2005) Autophagy in chronically ischemic myocardium. Proc Natl Acad Sci U S A 102:13807–13812PubMedCrossRef

34.

Zhai P, Galeotti J, Sadoshima J (2010) Inhibition of glycogen synthase kinase 3 protects against ischemia-reperfusion injury but exacerbates prolonged ischemic injury through modulating autophagy and mammalian target of rapamycin. Circ Res 105:e11

35.

Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283:10892–10903PubMedCrossRef

36.

Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT, Heintz N, Yue Z (2009) Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol 11:468–476PubMedCrossRef

Title: Is Autophagy in Response to Ischemia and Reperfusion Protective or Detrimental for the Heart?
Authors: Sebastiano Sciarretta
Nirmala Hariharan
Yoshiya Monden
Daniela Zablocki
Junichi Sadoshima
Publication date: 01-03-2011
Publisher: Springer-Verlag
Published in: Pediatric Cardiology / Issue 3/2011
Print ISSN: 0172-0643
Electronic ISSN: 1432-1971
DOI: https://doi.org/10.1007/s00246-010-9855-x

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Is Autophagy in Response to Ischemia and Reperfusion Protective or Detrimental for the Heart?

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2011

Rho-Kinase in Development and Heart Failure: Insights From Genetic Models

Cardiomyopathy of Friedreich’s Ataxia: Use of Mouse Models to Understand Human Disease and Guide Therapeutic Development

Role of Caveolae in Cardiac Protection

Engineered Human Cardiac Tissue

The Mitochondrial Permeability Transition Pore and the Cardiac Necrotic Program

Akt2: A Critical Regulator of Cardiomyocyte Survival and Metabolism

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page