Effect of Cnn1 Knockout on Aortic Smooth Muscle Cell Transcriptome
Smooth muscle cell (SMC) contraction and vascular tone are modulated by phosphorylation and multiple modifications of the thick filament. Thin filament regulation of SMC contraction has been reported to involve extracellular regulated kinase (ERK). Previous studies suggest that the actin-binding protein, calponin 1 (CNN1), acts as a scaffold linking protein kinase C (PKC), Raf, MEK, and ERK, promoting PKC-dependent ERK activation. To definitively test this hypothesis, and to gain further insight into the role of CNN1 in ERK activation and the regulation of SMC contractility, we generated a novel Calponin 1 knockout mouse (Cnn1 KO) by a single base substitution in an intronic CArG box that abolishes expression of CNN1 in a vascular SMC-restricted manner. Using this new Cnn1 KO mouse, we show that ablation of CNN1 has two effects, depending on the cytosolic free calcium level: (1) a reduced amplitude of stress and stiffness but an increase in agonist-induced ERK activation in the presence of elevated intracellular calcium caused by agonist stimulation; and (2) an increased duration of SM tone maintenance during intracellular calcium depletion, in the presence of an agonist. Together, these results indicate that CNN1 plays an important and complex modulatory role in SMC contractile tone amplitude and maintenance. Overall design: Differential gene expression in the aorta of Cnn1 KO mice