Skip to main content
  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

  • Home
  • About this Journal
    • General Statistics
    • Editorial Board
    • Editors
    • Information for Advertisers
    • Author Reprints
    • Commercial Reprints
    • Customer Service and Ordering Information
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • AHA Guidelines and Statements
    • Acknowledgment of Reviewers
    • Clinical Implications
    • Clinical-Pathological Conferences
    • Controversies in Hypertension
    • Editors' Picks
    • Guidelines Debate
    • Meeting Abstracts
    • Recent Advances in Hypertension
    • SPRINT Trial: the Conversation Continues
  • Resources
    • Instructions to Reviewers
    • Instructions for Authors
    • →Article Types
    • → Submission Guidelines
      • Research Guidelines
        • Minimum Information About Microarray Data Experiments (MIAME)
      • Abstract
      • Acknowledgments
      • Clinical Implications (Only by invitation)
      • Conflict(s) of Interest/Disclosure(s) Statement
      • Figure Legends
      • Figures
      • Novelty and Significance: 1) What Is New, 2) What Is Relevant?
      • References
      • Sources of Funding
      • Tables
      • Text
      • Title Page
      • Online/Data Supplement
    • →Tips for Easier Manuscript Submission
    • → General Instructions for Revised Manuscripts
      • Change of Authorship Form
    • → Costs to Authors
    • → Open Access, Repositories, & Author Rights Q&A
    • Permissions to Reprint Figures and Tables
    • Journal Policies
    • Scientific Councils
    • AHA Journals RSS Feeds
    • International Users
    • AHA Newsroom
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
  • Facebook
  • Twitter

  • My alerts
  • Sign In
  • Join

  • Advanced search

Header Publisher Menu

  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

Hypertension

  • My alerts
  • Sign In
  • Join

  • Facebook
  • Twitter
  • Home
  • About this Journal
    • General Statistics
    • Editorial Board
    • Editors
    • Information for Advertisers
    • Author Reprints
    • Commercial Reprints
    • Customer Service and Ordering Information
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • AHA Guidelines and Statements
    • Acknowledgment of Reviewers
    • Clinical Implications
    • Clinical-Pathological Conferences
    • Controversies in Hypertension
    • Editors' Picks
    • Guidelines Debate
    • Meeting Abstracts
    • Recent Advances in Hypertension
    • SPRINT Trial: the Conversation Continues
  • Resources
    • Instructions to Reviewers
    • Instructions for Authors
    • →Article Types
    • → Submission Guidelines
    • →Tips for Easier Manuscript Submission
    • → General Instructions for Revised Manuscripts
    • → Costs to Authors
    • → Open Access, Repositories, & Author Rights Q&A
    • Permissions to Reprint Figures and Tables
    • Journal Policies
    • Scientific Councils
    • AHA Journals RSS Feeds
    • International Users
    • AHA Newsroom
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
Editorial Commentaries

Angiotensin Receptors and Autophagy

Live and Let Die

U. Muscha Steckelings, Thomas Unger
Download PDF
https://doi.org/10.1161/HYPERTENSIONAHA.109.131425
Hypertension. 2009;53:898-899
Originally published May 20, 2009
U. Muscha Steckelings
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Thomas Unger
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Tables
  • Info & Metrics
  • eLetters

Jump to

  • Article
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Tables
  • Info & Metrics
  • eLetters
Loading

The renin-angiotensin system (RAS) and autophagy are both essentially involved in the pathomechanisms of various cardiovascular pathologies, eg, cardiac hypertrophy/load-induced heart disease, ischemic heart disease, or atherosclerosis.1–4 Regarding the RAS, it is commonly accepted that angiotensin II via the angiotensin II type 1 receptor (AT1R) directly and indirectly (by increasing blood pressure) contributes to, eg, cardiomyocyte hypertrophy, interstitial fibrosis, inflammation, oxidative stress, or apoptosis in cardiac pathologies, thereby promoting disease.1,5 In contrast, regarding the angiotensin II type 2 receptor (AT2R), the majority of data points to a tissue-protective effect of this receptor in cardiac disease because of its antifibrotic, anti-inflammatory, and antiapoptotic features. However, some publications also report a prohypertrophic effect of the AT2R in the heart. Because the determination of “true” AT2R-mediated effects is still difficult and experimental approaches are often indirect (inhibition experiments using the AT2R antagonist PD123319) and/or make use of genetically altered animals or cells, the true nature of AT2R-mediated effects in cardiac diseases is probably not yet completely understood.

Autophagy represents a highly conserved process for the lysosomal degradation of cytoplasmatic long-lived proteins and organelles.6 It can result in final decomposition of proteins contributing to a certain form of programmed cell death (autophagic cell death), but it may also serve as a survival mechanism by intracellular clearance of toxic or damaged proteins and organelles or, in times of starvation, through protein recycling and maintenance of intermediary metabolism.6 During autophagy, autophagosomes are built from so-called isolated membranes to sequestrate cytosolic constituents for later degradation (Figure). The whole process of autophagy is controlled by a set of autophagy-related genes (Atgs). One of these, Beclin-1 (Atg6), together with class III phosphoinositide 3-kinase, is needed for the vesicle nucleation of autophagosomes. Vesicle elongation requires 2 conjugation pathways, one of them involving microtubule-associated protein 1 light chain 3, which, during the process of elongation, is converted from its soluble form into a vesicle associated form. Both, vesicle-associated microtubule-associated protein 1 light chain 3 and Beclin-1 are main experimental markers for autophagy. After compartmentalization of proteins into autophagosomes, the autophagosomes fuse with lysosomes to form autolysosomes in which the phagosomal cargo is eventually degraded (Figure).

Figure1
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure. The process of autophagy and its modulation by AT1R and AT2R. Autophagy is initiated by formation of so-called isolation membranes, which sequestrate large proteins or organelles for later degradation. Expansion of the isolation membrane and enclosure of the cytoplasmic cargo lead to formation of autophagic vacuoles, the autophagosomes. Autophagosomes dock and fuse to lysosomes to form autolysosomes in which the cargo is eventually degraded. Porrello et al7 report in this issue of Hypertension that autophagy is promoted by angiotensin via the AT1R but is diminished via the AT2R. Adapted from Reference 6.

Although in the heart autophagy is part of the physiological turnover of organelles at low basal levels, autophagic processes in cardiomyocytes are clearly upregulated in response to stresses, eg, cardiac remodeling/hypertrophy or ischemic disease.2–4 However, for a long time it was not clear whether this increased autophagic response is a sign of failed cardiomyocyte repair or a suicide pathway for failing cardiomyocytes and whether autophagy should be regarded as a protective mechanism or a process contributing to disease progression. Current evidence supports the view that a physiological baseline autophagic activity is important for cellular homeostasis, whereas excessive autophagy is rather detrimental and to be eliminated in the clinical setting.4

Taking into account that the RAS and autophagy have both been clearly identified to be of major importance in cardiovascular pathologies, it seems only logical to look for an interaction between these 2 mechanisms. However, because scientists nowadays are usually very much specialized in a certain, defined area of research (which is a necessity because of the enormous amount of data), it needs people who look beyond the horizon of their daily, defined field of research to reveal connections and relationships between seemingly unrelated biological systems. The main achievement of the article by Porrello et al7 published in this issue of Hypertension is that it bridges the gap between the 2 biological systems of RAS and autophagy and provides first evidence for an interplay between these 2 systems in cardiomyocytes. Porrello et al7 report that neonatal rat cardiomyocytes overexpressing either the AT1R or the AT2R or both after adenoviral transfection present with either an augmented (via the AT1R) or inhibited (via the AT2R) autophagic response on stimulation by angiotensin II (Figure). Their finding is based on the determination of the number of autophagosomes labeled by fluorescent HcRed microtubule-associated protein 1 light chain 3. Cardiomyocytes derived from a genetic model of disturbed heart growth in rats (hypertrophic heart rat) were more susceptible to AT1R-induced autophagy but also showed a strong reduction of autophagic activity via the AT2R. The authors concluded that autophagy in cardiomyocytes is reciprocally regulated by AT1R and AT2R and suggested that the AT2R may be a novel therapeutic target in autophagic cardiomyopathies.

The results by Porrello et al7 open a completely new field of angiotensin research and will certainly stimulate many other researchers to look into interactions between autophagy and the RAS in various cardiovascular diseases. Presumably, it will not take long until the major findings by Porrello et al,7 a stimulatory effect on autophagy by the AT1R and inhibition of autophagy via the AT2R, will be validated by other groups. Confirmation of these data will be important in particular in experiments using primary (not genetically altered) cells, because artificially modified receptor expression levels may have an impact on receptor heterodimerization or other receptor-protein interactions resulting in altered receptor signaling. Further in vivo studies to corroborate an interaction between RAS and autophagy are needed even more, because although the study by Porrello et al7 is composed of some in vivo data, conclusive insights into the interaction between RAS and autophagy are solely derived from in vitro experiments in cardiomyocytes. For example, although the authors confirmed an increased autophagic response in cardiac ischemia reperfusion (increase in Beclin-1 and microtubule-associated protein 1 light chain 3, which was more pronounced in the hypertrophic heart rat compared with the normal heart rat), the impact of the RAS in this setting remains unclear and needs further investigation.

Nevertheless, this first description of a regulation of autophagic activity by angiotensin II with reciprocal effects depending on the angiotensin receptor subtype involved is an observation of absolute novelty and importance. Given the fact that autophagy and RAS are both involved in many physiological and pathophysiological processes as divergent as fetal development, neurodegeneration, ischemic tissue damage, aging, cancer, or keratinocyte differentiation,8,9 understanding the interaction between RAS and autophagy may be a key to improved understanding not just of hypertrophic or ischemic cardiac disease but also of many more pathological conditions.

Acknowledgments

Disclosures

None.

Footnotes

  • The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

  1. ↵
    de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T, for the International Union of Pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev. 2000; 52: 415–472.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    Rothermel BA, Hill JA. Autophagy in load-induced heart disease. Circ Res. 2008; 103: 1363–1369.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    Gustafsson AB, Gottlieb RA. Autophagy in ischemic heart disease. Circ Res. 2009; 104: 150–158.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    Nishida K, Kyoi S, Yamaguchi O, Sadoshima J, Otsu K. The role of autophagy in the heart. Cell Death Differ. 2009; 16: 31–38.
    OpenUrlCrossRefPubMed
  5. ↵
    Unger T, Li J. The role of the renin-angiotensin-aldosterone system in heart failure. J Renin Angiotensin Aldosterone Syst. 2004; 5 (suppl 1): S7–S10.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    Baehrecke EH. Autophagy: dual roles in life and death? Nature Rev Mol Cell Biol. 2005; 6: 505–510.
    OpenUrlCrossRefPubMed
  7. ↵
    Porrello ER, D'Amore A, Curl CL, Allen AM, Harrap SB, Thomas WG, Delbridge LMD. Angiotensin II type 2 receptor antagonizes angiotensin II type 1 receptor–mediated cardiomyocyte autophagy. Hypertension. 2009; 53: 1032–1040.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    Shintani T, Klionsky DJ. Autophagy in health and disease: a double-edged sword. Science. 2004; 306: 990–995.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Haruna K, Suga Y, Muramatsu S, Taneda K, Mizuno Y, Ikeda S, Ueno T, Kominami E, Tanida I, Tanida I, Hanada K. Differentiation-specific expression and localization of an autophagosomal marker protein (LC3) in human epidermal keratinocytes. J Dermatol Sci. 2008; 52: 213–215.
    OpenUrlCrossRefPubMed
View Abstract
Back to top
Previous ArticleNext Article

This Issue

Hypertension
June 2009, Volume 53, Issue 6
  • Table of Contents
Previous ArticleNext Article

Jump to

  • Article
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Tables
  • Info & Metrics
  • eLetters

Article Tools

  • Print
  • Citation Tools
    Angiotensin Receptors and Autophagy
    U. Muscha Steckelings and Thomas Unger
    Hypertension. 2009;53:898-899, originally published May 20, 2009
    https://doi.org/10.1161/HYPERTENSIONAHA.109.131425

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
  •  Download Powerpoint
  • Article Alerts
    Log in to Email Alerts with your email address.
  • Save to my folders

Share this Article

  • Email

    Thank you for your interest in spreading the word on Hypertension.

    NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

    Enter multiple addresses on separate lines or separate them with commas.
    Angiotensin Receptors and Autophagy
    (Your Name) has sent you a message from Hypertension
    (Your Name) thought you would like to see the Hypertension web site.
  • Share on Social Media
    Angiotensin Receptors and Autophagy
    U. Muscha Steckelings and Thomas Unger
    Hypertension. 2009;53:898-899, originally published May 20, 2009
    https://doi.org/10.1161/HYPERTENSIONAHA.109.131425
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Related Articles

Cited By...

Subjects

  • Intervention, Surgery, Transplantation
    • Pharmacology
  • Basic, Translational, and Clinical Research
    • Metabolism
    • ACE/Angiotensin Receptors/Renin Angiotensin System

Hypertension

  • About Hypertension
  • Instructions for Authors
  • AHA CME
  • Guidelines and Statements
  • Permissions
  • Journal Policies
  • Email Alerts
  • Open Access Information
  • AHA Journals RSS
  • AHA Newsroom

Editorial Office Address:
7272 Greenville Ave.
Dallas, TX 75231
email: hypertension@heart.org

Information for:
  • Advertisers
  • Subscribers
  • Subscriber Help
  • Institutions / Librarians
  • Institutional Subscriptions FAQ
  • International Users
American Heart Association Learn and Live
National Center
7272 Greenville Ave.
Dallas, TX 75231

Customer Service

  • 1-800-AHA-USA-1
  • 1-800-242-8721
  • Local Info
  • Contact Us

About Us

Our mission is to build healthier lives, free of cardiovascular diseases and stroke. That single purpose drives all we do. The need for our work is beyond question. Find Out More about the American Heart Association

  • Careers
  • SHOP
  • Latest Heart and Stroke News
  • AHA/ASA Media Newsroom

Our Sites

  • American Heart Association
  • American Stroke Association
  • For Professionals
  • More Sites

Take Action

  • Advocate
  • Donate
  • Planned Giving
  • Volunteer

Online Communities

  • AFib Support
  • Garden Community
  • Patient Support Network
  • Professional Online Network

Follow Us:

  • Follow Circulation on Twitter
  • Visit Circulation on Facebook
  • Follow Circulation on Google Plus
  • Follow Circulation on Instagram
  • Follow Circulation on Pinterest
  • Follow Circulation on YouTube
  • Rss Feeds
  • Privacy Policy
  • Copyright
  • Ethics Policy
  • Conflict of Interest Policy
  • Linking Policy
  • Diversity
  • Careers

©2018 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. The American Heart Association is a qualified 501(c)(3) tax-exempt organization.
*Red Dress™ DHHS, Go Red™ AHA; National Wear Red Day ® is a registered trademark.

  • PUTTING PATIENTS FIRST National Health Council Standards of Excellence Certification Program
  • BBB Accredited Charity
  • Comodo Secured