Activation of adenosine receptors improved cardiac dysfunction induced by myocardial infarction

Abstract

Abstract Introduction Acute myocardial infarction (MI) is characterized by an intense inflammatory response leading to cardiac remodeling and subsequent cardiac dysfunction. Purpose Activation of adenosine A2A and A3 receptors induced by LASSBio-1027 could improve cardiac function, through the reduction of the inflammatory response and the activated cardiac fibroblasts (CF). Methods The Animal Care and Use Committee approved the experimental protocols. MI was induced in male Wistar rats by ligation of the anterior descending coronary artery and confirmed by transthoracic echocardiography. The experimental groups were Sham and MI treated orally with either vehicle or LASSBio-1027 (30 or 70 μmol/kg) during 7 days. At the endpoint, hemodynamic parameters were evaluated and hearts were prepared for histological and immunohistochemical analysis for fibrosis and cellular infiltrate detection and for α-SMA, TNF-α, iNOs, c-fos, p38MAPK expression, respectively. Production of reactive oxygen species and collagen in CF with H2O2–induced oxidative stress was observed in the presence or absence of LASSBio-1027 (10 μM). Results Diastolic dysfunction was detected in MI group because the filling pressure (E/e') and the left ventricular end diastolic pressure (LVEDP) were increased from 22.9±1.6 to 37.0±3.7 and from 3.2±0.9 to 18.2±2.2 mmHg (p<0.01), respectively. LASSBio-1027 (70 μmol/kg) prevented diastolic dysfunction since E/e' and LVEDP reduced to 23.8±5.3 and 6.4±1.6 mmHg (p<0.01). Adenosine receptor agonist improved systolic dysfunction in MI group with increase of ejection fraction from of 30.1±3.1 to 48.4±4.8% (p<0.05). As shown in figure 1, MI promoted an increase in collagen deposition, cellular infiltrate, expression of SMA-α, TNF-α, iNOs, c-fos and p38MAPK which confirmed the intense fibrosis, cell proliferation and inflammation. Oral administration of LASSBio-1027 reduced those parameters in a dose dependent manner. LASSBio-1027 reduced H2O2-induced fibroblast-myofibroblast transformation with the decrease of stain density of α-SMA from 1794.4 to 574.4 staining area/cell and collagen production from 33.7±9.6 to 22.1±18.9% (p<0.05). Effects of LASSBio-1027 were inhibited by the antagonists of A2A (ZM-241385) and A3 (MRE3008F20) receptors. Conclusions Activation of adenosine A2A and A3 receptors by LASSBio-1027 improved cardiac function and remodeling induced by MI. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): CNPq. CAPES, FAPERJ Histological AnalysisImmunohistochemistry analysis