Overexpression of Brain Natriuretic Peptide Facilitates Neutrophil Infiltration and Cardiac Matrix Metalloproteinase-9 Expression After Acute Myocardial Infarction

Abstract

Background-Recent clinical trials have shown that systemic infusion of nesiritide, a recombinant human brain natriuretic peptide (BNP), improves hemodynamic parameters in acutely decompensated hearts. This suggests that BNP exerts a direct cardioprotective effect and might thus be a useful therapeutic agent with which to treat acute myocardial infarction (MI). In the present study, we used BNP-transgenic (BNP-Tg) mice with elevated plasma BNP to determine whether and how BNP contributes to left ventricular remodeling and healing after MI. Methods and Results-We examined the accumulation of neutrophils and the expression and activation of matrix metalloproteinase (MMP)-9 in the ventricles of male BNP-Tg mice and their nontransgenic (non-Tg) littermates during the early phase after acute MI. The numbers of neutrophils infiltrating the infarcted area were significantly increased in BNP-Tg mice 3 days after MI. In addition, both the gene expression and zymographic activity of MMP-9, but not MMP-2, were significantly higher in BNP-Tg than non-Tg mice. Double immunostaining revealed that neutrophils are the main source of the MMP-9, although doxycycline, an MMP inhibitor, had no effect on neutrophil infiltration of the infarcted area in BNP-Tg mice. Conclusions-These results demonstrate that elevated plasma BNP facilitates neutrophil infiltration of the infarcted area after MI and increases the activity of the MMP-9 they produce. This suggests that BNP plays a key role in the processes of extracellular matrix remodeling and wound-healing during the early phase after acute MI.

Atrial natriuretic peptide increases inflammation, infarct size, and mortality after experimental coronary occlusion

“…There have been no previous studies that have investigated the effect of ANP on myocardial ischemia without reperfusion. However, in a model of acute MI similar to ours, an overexpression of brain natriuretic peptide (BNP) increased neutrophil infiltration, which is consistent with the proinflammatory effects of ANP we observed in these experiments (20). In a model of acute MI followed by reperfusion, mice lacking the GC-A receptor (the receptor for both ANP and BNP) had smaller infarcts and decreased neutrophil infiltrates in the myocardium, though a survival advantage was not shown.…”

Recombinant human brain natriuretic peptide therapy combined with bone mesenchymal stem cell transplantation for treating heart failure in rats

“…In addition, rhBNP inhibits sodium reabsorption in the proximal tubules, which generates a natriuretic effect and further reduces the cardiac preload by enhancing the glomerular filtration rate (17)(18)(19). rhBNP is also an antagonist of the renin-angiotensin-aldosterone system (RAAS) and it reduces the excessive activation of renin, aldosterone, endothelin and vasopressin to relieve their adverse effects (20,21). rhBNP is involved in the regulation of blood pressure, blood volume and the water and electrolyte balance.…”

Matrix metalloproteinases and myocardial infarction

“…Furthermore, necrotic cardiomyocytes were not removed, and the formation of granulation and fibrous tissue did not occur in these mice (31,32). Elevated plasma brain natriuretic peptide levels have been shown to cause an increase in MMP-9 activity (33). At this time, few data are available regarding the factors that control MMPs.…”