Cholinergic inhibitory regulation of MMP activity in neonatal cardiac fibroblasts

Abstract

Altered cardiac fibroblast function and extracellular matrix (ECM) homeostasis are the major processes during cardiac remodeling. The impaired autonomic balance and sustained sympatho-excitation may contribute to these adverse alterations. In this study, we investigated the effect of cholinergic activity on fibroblast proliferation, collagen production, and metalloproteinase (MMP) activity in vitro using primary cultured rat neonatal cardiac fibroblast cells. The treatment with an adrenergic agonist, phenylephrine (PE, 10 uM), increased MMP9 activity, reaching 132±3 % of the control. Co-treatment with a cholinergic agonist bethanechol (Beth, 10 uM) reversed PE-induced increase in MMP9 activity, down to 93±5 % of the control. Beth alone did not exhibit a significant effect on MMP9 activity. Furthermore, PE increased collagen production, up to 178±16 % of the control, which was also reversed by Beth to 106±4 % of the control. Neither PE nor Beth induced significant changes in fibroblast proliferation in this study. These results suggest that parasympathetic cholinergic action may play a protective role in cardiac remodeling. This work was supported by American Heart Association Beginning Grant-in Aid No. 0460063Z, NIH INBRE Grant No. 2 P20 RR016479, and NIH COBRE grant No. 5 P20 RR017662