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

Caroline Fattah; Katrin Nather; Charlotte S. McCarroll; Maria P. Hortigon-Vinagre; Victor Zamora; Monica Flores-Munoz; Lisa McArthur; Lorena Zentilin; Mauro Giacca; Rhian M. Touyz; Godfrey L. Smith; Christopher M. Loughrey; Stuart A. Nicklin

doi:10.1016/j.jacc.2016.09.946

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

Caroline Fattah, Katrin Nather, Charlotte S. McCarroll, Maria P. Hortigon-Vinagre, Victor Zamora, Monica Flores-Munoz, Lisa McArthur, Lorena Zentilin, Mauro Giacca, Rhian M. Touyz, Godfrey L. Smith, Christopher M. Loughrey, Stuart A. Nicklin^*

^*Corresponding author for this work

Cardiovascular Medicine & Sciences

Research output: Contribution to journal › Article › peer-review

39 Citations (Scopus)

Abstract

Background Angiotensin-(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). Objectives The authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and functional remodeling post-infarction. Methods C57BL/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. Results Gene 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. Conclusions Our 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.

Original language	English
Pages (from-to)	2652-2666
Number of pages	15
Journal	Journal of the American College of Cardiology
Volume	68
Issue number	24
DOIs	https://doi.org/10.1016/j.jacc.2016.09.946
Publication status	Published - 20 Dec 2016

Keywords

adeno-associated virus
calcium
inotropy
renin angiotensin system

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jacc.2016.09.946

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Fattah, C., Nather, K., McCarroll, C. S., Hortigon-Vinagre, M. P., Zamora, V., Flores-Munoz, M., McArthur, L., Zentilin, L., Giacca, M., Touyz, R. M., Smith, G. L., Loughrey, C. M., & Nicklin, S. A. (2016). Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction. Journal of the American College of Cardiology, 68(24), 2652-2666. https://doi.org/10.1016/j.jacc.2016.09.946

@article{99b837e6b1bf49918a7937be5a0f878c,

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

abstract = "Background Angiotensin-(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). Objectives The authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and functional remodeling post-infarction. Methods C57BL/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. Results Gene 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. Conclusions Our 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.",

keywords = "adeno-associated virus, calcium, inotropy, renin angiotensin system",

author = "Caroline Fattah and Katrin Nather and McCarroll, {Charlotte S.} and Hortigon-Vinagre, {Maria P.} and Victor Zamora and Monica Flores-Munoz and Lisa McArthur and Lorena Zentilin and Mauro Giacca and Touyz, {Rhian M.} and Smith, {Godfrey L.} and Loughrey, {Christopher M.} and Nicklin, {Stuart A.}",

year = "2016",

month = dec,

day = "20",

doi = "10.1016/j.jacc.2016.09.946",

language = "English",

volume = "68",

pages = "2652--2666",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier USA",

number = "24",

}

Fattah, C, Nather, K, McCarroll, CS, Hortigon-Vinagre, MP, Zamora, V, Flores-Munoz, M, McArthur, L, Zentilin, L, Giacca, M, Touyz, RM, Smith, GL, Loughrey, CM & Nicklin, SA 2016, 'Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction', Journal of the American College of Cardiology, vol. 68, no. 24, pp. 2652-2666. https://doi.org/10.1016/j.jacc.2016.09.946

TY - JOUR

T1 - Gene Therapy With Angiotensin-(1-9) Preserves Left Ventricular Systolic Function After Myocardial Infarction

AU - Fattah, Caroline

AU - Nather, Katrin

AU - McCarroll, Charlotte S.

AU - Hortigon-Vinagre, Maria P.

AU - Zamora, Victor

AU - Flores-Munoz, Monica

AU - McArthur, Lisa

AU - Zentilin, Lorena

AU - Giacca, Mauro

AU - Touyz, Rhian M.

AU - Smith, Godfrey L.

AU - Loughrey, Christopher M.

AU - Nicklin, Stuart A.

PY - 2016/12/20

Y1 - 2016/12/20

N2 - Background Angiotensin-(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). Objectives The authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and functional remodeling post-infarction. Methods C57BL/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. Results Gene 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. Conclusions Our 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.

AB - Background Angiotensin-(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). Objectives The authors evaluated effects of Ang-(1-9) gene therapy on myocardial structural and functional remodeling post-infarction. Methods C57BL/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. Results Gene 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. Conclusions Our 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.

KW - adeno-associated virus

KW - calcium

KW - inotropy

KW - renin angiotensin system

UR - http://www.scopus.com/inward/record.url?scp=85003844969&partnerID=8YFLogxK

U2 - 10.1016/j.jacc.2016.09.946

DO - 10.1016/j.jacc.2016.09.946

M3 - Article

C2 - 27978950

AN - SCOPUS:85003844969

SN - 0735-1097

VL - 68

SP - 2652

EP - 2666

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 24

ER -

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

Abstract

Keywords

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