Metoprolol Treatment Lowers Thrombospondin‐4 Expression in Rats with Myocardial Infarction and Left Ventricular Hypertrophy

Abstract: Thrombospondins are matrix proteins linked to extracellular matrix remodelling but their precise role in the heart is not known. In this study, we characterised left ventricular thrombospondin‐1 and ‐4 expression in rats treated with a beta‐blocker metoprolol during the remodelling process in response to pressure overload and acute myocardial infarction. Left ventricular thrombospondin‐1 and thrombospondin‐4 mRNA levels increased 8.4‐fold (p < 0.001) and 7.3‐fold (p < 0.001) post‐infarction, respectively. Metoprolol infusion by osmotic minipumps (1.5 mg/kg/hr) for 2 weeks after myocardial infarction decreased thrombospondin‐1 and thrombospondin‐4 mRNA levels (55% and 50%, respectively), improved left ventricular function, and attenuated left ventricular remodelling with reduction of left ventricular atrial natriuretic peptide and brain natriuretic peptide gene expression. Thrombospondin‐1 and ‐4 mRNA levels correlated positively with echocardiographic parameters of left ventricular remodelling as well as with atrial natriuretic peptide and brain natriuretic peptide gene expression. Moreover, there was a negative correlation between left ventricular ejection fraction and thrombospondin‐1 mRNA levels. In 12‐month‐old spontaneously hypertensive rats with left ventricular hypertrophy, metoprolol decreased left ventricular thrombospondin‐4 levels and attenuated remodelling while thrombospondin‐1, atrial natriuretic peptide and brain natriuretic peptide mRNA levels as well as left ventricular function remained unchanged. In metoprolol‐treated spontaneously hypertensive rats, thrombospondin‐4 gene expression correlated with parameters of left ventricular remodelling, while no correlations between thrombospondins and natriuretic peptides were observed. These results indicate that thrombospondin‐1 expression is linked exclusively to left ventricular remodelling process post‐infarction while thrombospondin‐4 associates with myocardial remodelling both after myocardial infarction and in hypertensive heart disease suggesting that thrombospondins may have unique roles in extracellular matrix remodelling process.