Angiotensin type 1a receptor-deficient mice develop diabetes-induced cardiac dysfunction, which is prevented by renin-angiotensin system inhibitors

Cardiovascular Diabetology

Original Investigation

Kenneth M Baker¹  Rajesh Kumar¹  Candice M Thomas¹  Qian Chen Yong¹  Niketa Chandel¹  Rachid Seqqat² 

[1] Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center, College of Medicine; Scott & White; Central Texas Veterans Health Care System, 1901 South First Street, Building 205, Temple, 76504, Texas, USA;Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center, College of Medicine; Scott & White; Central Texas Veterans Health Care System, 1901 South First Street, Building 205, Temple, 76504, Texas, USA;SENESCYT/Proyecto Prometeo, Laboratorio de Biotecnología Humana, Escuela Politécnica del Ejército, Sangolquí, Ecuador;

关键词: Renin-angiotensin system;    Intracrine;    Renin inhibitor;    Diabetic cardiomyopathy kallikrein;    Kininogen;    Kinin B2 receptor;   

DOI  :  10.1186/1475-2840-12-169

 received in 2013-09-25, accepted in 2013-11-09,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundDiabetes-induced organ damage is significantly associated with the activation of the renin-angiotensin system (RAS). Recently, several studies have demonstrated a change in the RAS from an extracellular to an intracellular system, in several cell types, in response to high ambient glucose levels. In cardiac myocytes, intracellular angiotensin (ANG) II synthesis and actions are ACE and AT1 independent, respectively. However, a role of this system in diabetes-induced organ damage is not clear.MethodsTo determine a role of the intracellular ANG II in diabetic cardiomyopathy, we induced diabetes using streptozotocin in AT1a receptor deficient (AT1a-KO) mice to exclude any effects of extracellular ANG II. Further, diabetic animals were treated with a renin inhibitor aliskiren, an ACE inhibitor benazeprilat, and an AT1 receptor blocker valsartan.ResultsAT1a-KO mice developed significant diastolic and systolic dysfunction following 10 wks of diabetes, as determined by echocardiography. All three drugs prevented the development of cardiac dysfunction in these animals, without affecting blood pressure or glucose levels. A significant down regulation of components of the kallikrein-kinin system (KKS) was observed in diabetic animals, which was largely prevented by benazeprilat and valsartan, while aliskiren normalized kininogen expression.ConclusionsThese data indicated that the AT1a receptor, thus extracellular ANG II, are not required for the development of diabetic cardiomyopathy. The KKS might contribute to the beneficial effects of benazeprilat and valsartan in diabetic cardiomyopathy. A role of intracellular ANG II is suggested by the inhibitory effects of aliskiren, which needs confirmation in future studies.

【 授权许可】

Unknown   
© Yong et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.