title: Novel Cardiac Intracrine Mechanisms Based on Ang-(1-12)/Chymase Axis Require a Revision of Therapeutic Approaches in Human Heart Disease.
abstract: OBJECTIVE
  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).
  
  
  RESULTS
  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. 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.
authors.affiliation: Department of General Surgery, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Santiago
authors.initials: S
authors.lastname: Reyes
authors.affiliation: Department of General Surgery, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.|Cardiovascular Sciences Center, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Jasmina
authors.initials: J
authors.lastname: Varagic
authors.affiliation: Department of General Surgery, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Sarfaraz
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Department of General Surgery, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.|Cardiovascular Sciences Center, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: VonCannon
authors.affiliation: Department of Cardiothoracic Surgery, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Neal D
authors.initials: ND
authors.lastname: Kon
authors.affiliation: Department of Anesthesiology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.|Department of Internal Medicine-Molecular Medicine, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Cardiovascular Sciences Center, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.|Department of Anesthesiology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Leanne
authors.initials: L
authors.lastname: Groban
authors.affiliation: Department of Internal Medicine-Cardiovascular Medicine, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.
authors.forename: Che Ping
authors.initials: CP
authors.lastname: Cheng
authors.affiliation: Departments of Cell Biology, Microbiology and Physiology; and Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA.|Department of Veterans Affairs, Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Dell'Italia
authors.affiliation: Department of General Surgery, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA. cferrari@wakehealth.edu.|Departments of Internal Medicine-Nephrology and Physiology-Pharmacology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157, USA. cferrari@wakehealth.edu.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Ferrario
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000808:Angiotensinogen / Q000378:metabolism*; D000818:Animals; D053818:Chymases / Q000378:metabolism*; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D010446:Peptide Fragments / Q000378:metabolism*; D011945:Receptors, Angiotensin / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D010446:Peptide Fragments; D011945:Receptors, Angiotensin; C000610416:angiotensin-(1-12), human; D000808:Angiotensinogen; D053818:Chymases
keywords: Angiotensin receptor blockers; Angiotensin-(1-12); Angiotensin-converting enzyme inhibitor; Cardiomyocyte; Chymase; Intracrine