Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction

Abstract

BackgroundAngiotensin-(1-9) [Ang-(1-9)] is a novel peptide of the counter-regulatory axis of the renin-angiotensin-aldosterone system previously demonstrated to have therapeutic potential in hypertensive cardiomyopathy when administered via osmotic mini-pump. Here, we investigate whether gene transfer of Ang-(1-9) is cardioprotective in a murine model of myocardial infarction (MI).ObjectivesThe authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and functional remodeling post-infarction.MethodsC57BL/6 mice underwent permanent left anterior descending coronary artery ligation and cardiac function was assessed using echocardiography for 8 weeks followed by a terminal measurement of left ventricular pressure volume loops. Ang-(1-9) was delivered by adeno-associated viral vector via single tail vein injection immediately following induction of MI. Direct effects of Ang-(1-9) on cardiomyocyte excitation/contraction coupling and cardiac contraction were evaluated in isolated mouse and human cardiomyocytes and in an ex vivo Langendorff-perfused whole-heart model.ResultsGene delivery of Ang-(1-9) reduced sudden cardiac death post-MI. Pressure volume measurements revealed complete restoration of end-systolic pressure, ejection fraction, end-systolic volume, and the end-diastolic pressure volume relationship by Ang-(1-9) treatment. Stroke volume and cardiac output were significantly increased versus sham. Histological analysis revealed only mild effects on cardiac hypertrophy and fibrosis, but a significant increase in scar thickness. Direct assessment of Ang-(1-9) on isolated cardiomyocytes demonstrated a positive inotropic effect via increasing calcium transient amplitude and contractility. Ang-(1-9) increased contraction in the Langendorff model through a protein kinase A–dependent mechanism.ConclusionsOur novel findings showed that Ang-(1-9) gene therapy preserved left ventricular systolic function post-MI, restoring cardiac function. Furthermore, Ang-(1-9) directly affected cardiomyocyte calcium handling through a protein kinase A–dependent mechanism. These data emphasized Ang-(1-9) gene therapy as a potential new strategy in the context of MI.

Counter-regulatory renin–angiotensin system in cardiovascular disease

“…In a study by Ocaranza and colleagues, administra tion of angiotensin 1-9 reduced blood pressure levels in hypertensive rats and attenuated myocardial damage by inhibiting the development of ventricular hypertro phy and fibrosis; importantly, these effects were medi ated through AT 2 R but not Mas receptor signalling 73 . However, in a separate study, gene delivery of angio tensin 1-9 with an adeno associated virus (AAV) in mice subjected to coronary artery ligation completely restored www.nature.com/nrcardio systolic blood pressure levels and cardiac output com pared with sham treated mice, but histological analy sis revealed only mild effects on cardiac hypertrophy and fibrosis 79 . Notably, Ocaranza and colleagues only evaluated angiotensin 1-9 administration for 2 weeks 73 , compared with the latter study that examined the effects of this peptide for 8 weeks 79 .…”

“…However, in a separate study, gene delivery of angio tensin 1-9 with an adeno associated virus (AAV) in mice subjected to coronary artery ligation completely restored www.nature.com/nrcardio systolic blood pressure levels and cardiac output com pared with sham treated mice, but histological analy sis revealed only mild effects on cardiac hypertrophy and fibrosis 79 . Notably, Ocaranza and colleagues only evaluated angiotensin 1-9 administration for 2 weeks 73 , compared with the latter study that examined the effects of this peptide for 8 weeks 79 . The conflicting findings between these two studies suggest that the attenuation of myocardial damage might be transient and not sus tained in the long term.…”

“…Administration of the AT 2 R agonist C21 to rats subjected to coronary artery ligation significantly improved recovery of left ventricular func tion and reduced cardiac remodelling after myocardial infarction 100 . Delivery of angiotensin 1-9 with an AAV vector into mice after the induction of myocardial infarc tion resulted in a reduction in sudden cardiac death and improved left ventricular function compared with con trol mice 79 . Importantly, angiotensin 1-9 had a positive inotropic effect, achieved by increasing calcium transient amplitude and contractility through a protein kinase A dependent mechanism 79 .…”

Classic and Nonclassic Renin-Angiotensin Systems in the Critically Ill

“…43 Angiotensin (1-9) is a nonapeptide generated by the ACE2-related breakdown of Ang I, acting as a competitor to ACE-related generation of Ang II. 44 It is a potent cardioprotective antifibrotic agent that binds the AT 2 R. 44,45 Angiotensin-Converting Enzyme 2 ACE2 is the pivotal enzyme of the nonclassic RAS. 10 ACE2 is transmembrane monocarboxypeptidase that converts Ang II into Ang (1-7) and Ang I into Ang (1)(2)(3)(4)(5)(6)(7)(8)(9).…”

Characterization of Recombinant Adeno-Associated Viral Transduction and Safety Profiles in Cardiomyocytes

“…A large number of genes or non-coding RNAs were unraveled to regulate the survival of cardiomyocytes, hence, those targets could be potential candidates for effective gene therapy of CVD [5][6][7].…”