Cardioprotection of controlled and cardiac-specific over-expression of A(2A)-adenosine receptor in the pressure overload.

Eman A Hamad,Walter Koch,Joseph Y Cheung,Weizhong Zhu,Tung O Chan,Valerie Myers,Xue-Qian Zhang,Erhe Gao,Jianliang Song,Jin Zhang,Arthur M Feldman,Xue Li,Piero Anversa

doi:10.1371/journal.pone.0039919

Eman A Hamad, Walter Koch + Show 11 more

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https://doi.org/10.1371/journal.pone.0039919

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Journal: PloS one	Publication Date: Jul 6, 2012
Citations: 65	License type: CC BY 4.0

Affiliation: Temple University, Jefferson College

Abstract

Adenosine binds to three G protein-coupled receptors (R) located on the cardiomyocyte (A1-R, A2A-R and A3-R) and provides cardiac protection during both ischemic and load-induced stress. While the role of adenosine receptor-subtypes has been well defined in the setting of ischemia-reperfusion, far less is known regarding their roles in protecting the heart during other forms of cardiac stress. Because of its ability to increase cardiac contractility and heart rate, we hypothesized that enhanced signaling through A2A-R would protect the heart during the stress of transverse aortic constriction (TAC). Using a cardiac-specific and inducible promoter, we selectively over-expressed A2A-R in FVB mice. Echocardiograms were obtained at baseline, 2, 4, 8, 12, 14 weeks and hearts were harvested at 14 weeks, when WT mice developed a significant decrease in cardiac function, an increase in end systolic and diastolic dimensions, a higher heart weight to body weight ratio (HW/BW), and marked fibrosis when compared with sham-operated WT. More importantly, these changes were significantly attenuated by over expression of the A2A-R. Furthermore, WT mice also demonstrated marked increases in the hypertrophic genes β-myosin heavy chain (β-MHC), and atrial natriuretic factor (ANF) – changes that are mediated by activation of the transcription factor GATA-4. Levels of the mRNAs encoding β-MHC, ANP, and GATA-4 were significantly lower in myocardium from A2A-R TG mice after TAC when compared with WT and sham-operated controls. In addition, three inflammatory factors genes encoding cysteine dioxygenase, complement component 3, and serine peptidase inhibitor, member 3N, were enhanced in WT TAC mice, but their expression was suppressed in A2A-R TG mice. A2A-R over-expression is protective against pressure-induced heart failure secondary to TAC. These cardioprotective effects are associated with attenuation of GATA-4 expression and inflammatory factors. The A2A-R may provide a novel new target for pharmacologic therapy in patients with cardiovascular disease.

Highlights

Adenosine is an endogenous purine nucleoside that plays an important role in protecting the heart during ischemia
The human A2A-AR cDNA was cloned into a cardiac-specific and inducible controlled vector (TREMHC) composed of a modified mouse a-myosin heavy chain (a-MHC) minimal promoter fused with nucleotide binding sites for tetracycline transactivating factor (Fig. 1A). [21] A2A-AR transgenic (TG) mice were engineered on an FVB background (PolyGene, Zurich, Switzerland) and crossed with mice that expressed tTA in the heart (MHC-tTA; Fig. 1A)
The present study demonstrates for the first time that activation of the A2A-R signaling pathway can modulate the fibrosis, hypertrophy and subsequent left ventricular dysfunction that follow transverse aortic constriction (TAC) using a murine model in which overexpression of the A2A receptor can be controlled and is cardiac specific

Summary

Introduction

Adenosine is an endogenous purine nucleoside that plays an important role in protecting the heart during ischemia. Studies using murine models in which the A1- and A3-Rs have been genetically manipulated demonstrate a critical role for these receptors in cardiac protection during ischemia and reperfusion. Owing at least in part to its pharmacological effects on neurohormone and cytokine activation, [8,9] adenosine affects ventricular remodeling in models of heart failure. Pharmacologic activation of the A1-R effectively attenuated the development of cardiac hypertrophy and prevented heart failure in mice that underwent transverse aortic constriction (TAC) [11] and mice that were A1-R gene-deficient had a higher mortality when compared with wild-type controls but did not demonstrate altered ventricular hypertrophy or increased cardiac dysfunction. [14] Surprisingly, mice in which the A3-R had been knocked out demonstrated an improved survival, decreased fibrosis and hypertrophy and a more robust left ventricular function after TAC when compared with wild-type controls. The role of the A2-R in cardiac remodeling has not been defined

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