New agonist of adenosine receptor (LASSBio-1027) improves cardiac remodeling induced by myocardial infarction

Abstract

Introduction: Prevention of cardiac remodeling induced by myocardial infarction (MI) is of great importance because it is one of the factors for the development of heart failure (HF). Thus, LASSBio-1027 was tested in acute model of MI due to its vasodilatory and anti-proliferative profile through the activation of adenosine A_2A and A₃ receptors.

Methods: Protocols were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. MI was induced in male Wistar rats (180-200 g) which were subjected to ligation of the anterior descending coronary artery under isoflorane anesthesia (3% v/v). Animals were randomly divided into groups treated orally (gavage) with either vehicle or LASSBio-1027 (30 and 70 umol/kg) for 7 days. All groups underwent echocardiographic analysis and anterior wall thickness (AWTd) during diastole; mitral flow using the ratio between early transmitral filling velocity (E) and tissue doppler (e^,) were determined. The border of infarcted area was used to evaluate interstitial cells and expression of alpha-SMA. Expression of TNF-alpha, SERCA2, p-ERK-1/2 and ERK-1/2 were also investigated. Results: MI reduced AWTd from 1.24 ± 0.17 to 0.42 ± 0.02 mm (P<0.01) which was recovered after treatment with LASSBio-1027. Mitral flow was increased from 22.9 ± 1.6 to 37.0 ± 3.6 (P<0.01) after experimental MI and reduced with LASSBio-1027. The ejection fraction in MI group was 36.6 ± 2.0% which was increased to 46.99 ± 7.40% after treatment (P<0.05). An increase of collagen deposition was observed in MI group of 33.35 ± 5.74% and treatment with LASSBio-1027 (70 µmol/kg) reduced to 14.50 ± 0.32% (P<0.05). LASSBio-1027 reduced interstitial cells from 275.5 ± 49.13 (MI group) to 110.1 ±17.09 (P<0.05). It was observed an increased alpha-SMA expression in the MI group with 36.83 ± 2.89% and a reduction after treatment with LASSBio-1027, 6.28 ± 4.12% and 14.01 ± 4.31%, for 30 and 70 µmol/kg. MI increased the expression of TNF-alpha, p-ERK1-2/ERK1-2 and SERCA2 in comparison to Sham. LASSBio-1027 at 30 μmol/kg recovered the expression of all proteins to control values.

Conclusion: LASSBio-1027 prevented the development of HF by improving cardiac remodeling after acute MI.