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Novel Cardiac Intracrine Mechanisms Based on Ang-(1-12)/Chymase Axis Require a Revision of Therapeutic Approaches in Human Heart Disease

  • Hypertension and the Kidney (RM Carey, Section Editor)
  • Published:
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Abstract

Purpose of the Review

Drugs targeting the renin-angiotensin system (RAS), namely angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, are the most commonly prescribed drugs for patients with or at risk for cardiovascular events. However, new treatment strategies aimed at mitigating the rise of the heart failure pandemic are warranted because clinical trials show that RAS blockers have limited benefits in halting disease progression. The main goal of this review is to put forward the concept of an intracrine RAS signaling through the novel angiotensin-(1-12)/chymase axis as the main source of deleterious angiotensin II (Ang II) in cardiac maladaptive remodeling leading to heart failure (HF).

Recent Findings

Expanding traditional knowledge, Ang II can be produced in tissues independently from the circulatory renin-angiotensin system. In the heart, angiotensin-(1-12) [Ang-(1-12)], a recently discovered derivative of angiotensinogen, is a precursor of Ang II, and chymase rather than ACE is the main enzyme contributing to the direct production of Ang II from Ang-(1-12). The Ang-(1-12)/chymase axis is an independent intracrine pathway accounting for the trophic, contractile, and pro-arrhythmic Ang II actions in the human heart. Ang-(1-12) expression and chymase activity have been found elevated in the left atrial appendage of heart disease subjects, suggesting a pivotal role of this axis in the progression of HF.

Summary

Recent meta-analysis of large clinical trials on the use of ACE inhibitors and angiotensin receptor blockers in cardiovascular disease has demonstrated an imbalance between patients that significantly benefit from these therapeutic agents and those that remain at risk for heart disease progression. Looking to find an explanation, detailed investigation on the RAS has unveiled a previously unrecognized complexity of substrates and enzymes in tissues ultimately associated with the production of Ang II that may explain the shortcomings of ACE inhibition and angiotensin receptor blockade. Discovery of the Ang-(1-12)/chymase axis in human hearts, capable of producing Ang II independently from the circulatory RAS, has led to the notion that a tissue-delimited RAS signaling in an intracrine fashion may account for the deleterious effects of Ang II in the heart, contributing to the transition from maladaptive cardiac remodeling to heart failure. Targeting intracellular RAS signaling may improve current therapies aimed at reducing the burden of heart failure.

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Abbreviations

RAS:

Renin-angiotensin system

ACE:

Angiotensin-converting enzyme

ARB:

Angiotensin II receptor blocker

Ang:

Angiotensin

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Authors and Affiliations

  1. Department of General Surgery, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Santiago Reyes, Jasmina Varagic, Sarfaraz Ahmad, Jessica VonCannon & Carlos M. Ferrario

  2. Cardiovascular Sciences Center, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Jasmina Varagic, Jessica VonCannon & Leanne Groban

  3. Department of Cardiothoracic Surgery, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Neal D. Kon

  4. Department of Anesthesiology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Hao Wang & Leanne Groban

  5. Department of Internal Medicine-Molecular Medicine, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Hao Wang

  6. Department of Internal Medicine-Cardiovascular Medicine, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Che Ping Cheng

  7. Departments of Cell Biology, Microbiology and Physiology; and Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA

    Louis J. Dell’Italia

  8. Department of Veterans Affairs, Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA

    Louis J. Dell’Italia

  9. Departments of Internal Medicine-Nephrology and Physiology-Pharmacology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Carlos M. Ferrario

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  1. Santiago Reyes
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Correspondence to Carlos M. Ferrario.

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Conflict of Interest

Dr. Ferrario reports grants from National Heart, Lung Blood Institute of the NIH; and personal fees from Sanofi and Daiichi Sankyo. Drs. Reyes, Varagic, Ahmad, VonCannon, Kon, Wang, Groban, Cheng, and Dell’Italia declare no conflicts of interest relevant to this manuscript.

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All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

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LIST OF MENTIONED DRUGS

– Angiotensin-converting enzyme inhibitors: captopril, lisinopril, ramipril, enalapril, perindopril, trandolapril

– Angiotensin-converting enzyme 2 inhibitors: MLN-4760

– Angiotensin II receptor blockers: losartan, candesartan, olmesartan, irbesartan, telmisartan, valsartan

– Chymase inhibitors: chymostatin

– Neprilysin inhibitors: SHC39370

This article is part of the Topical Collection on Hypertension and the Kidney

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Reyes, S., Varagic, J., Ahmad, S. et al. Novel Cardiac Intracrine Mechanisms Based on Ang-(1-12)/Chymase Axis Require a Revision of Therapeutic Approaches in Human Heart Disease. Curr Hypertens Rep 19, 16 (2017). https://doi.org/10.1007/s11906-017-0708-3

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