Early expression of monocyte chemoattractant protein-1 correlates with the onset of isoproterenol-induced cardiac fibrosis in rats with distinct angiotensin-converting enzyme polymorphism.

INTRODUCTION

Isoproterenol treatment of Brown Norway and Lewis rats (high and low plasma angiotensin-I-converting enzyme activity, respectively) results in similar cardiac hypertrophy but higher cardiac fibrosis in Brown Norway rats.

MATERIALS AND

METHODS

Rats were infused in vivo with isoproterenol for two or 10 days. Cardiac fibrosis and inflammation were evaluated histochemically. We measured the mRNAs of pro-fibrotic factors (transforming growth factor beta(1), endothelin-1) and pro-inflammatory factors (monocyte chemoattractant protein-1). In studies with cardiac fibroblasts incubated with isoproterenol in vitro , we measured cell proliferation, angiotensin-I-converting enzyme and matrix metalloprotease 2 activities and deposition of collagen type I and fibronectin.

RESULTS

After treatment with isoproterenol for two days, there were large areas of myocardial injury and numerous inflammatory foci in the left ventricle, these being greater in Brown-Norway than in Lewis rats. After treatment with isoproterenol for 10 days, there were large areas of damage with extensive collagen deposition only in the left ventricle; both strains exhibited this damage which was, however, more severe in Brown-Norway than in Lewis rats. After treatment with isoproterenol for two, but not 10, days, greater amounts of monocyte chemoattractant protein-1 mRNA were found in Brown Norway than in Lewis rats. Cell proliferation, activities of angiotensin-I-converting enzyme and matrix metalloprotease 2, amounts of collagen type I and fibronectin were similar in cardiac fibroblasts from both strains; changes after isoproterenol (10 microM) were also similar in both strains.

CONCLUSION

We conclude that the greater cardiac fibrosis in Brown Norway rats treated with isoproterenol correlates with the early and higher expression of proinflammatory factors.