Molecular mechanism of apoptosis and differentiation in vascular smooth muscle cells: the role of c-Jun N-terminal kinase (JNK)

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[ Aim ] Recent studies indicate that the phenotypic modulation and apoptosis of vascular smooth muscle are fundamental phenomena underlying atherosclerosis. Vascular smooth muscle cells change their phenotype from highly differentiated contractile phenotype that is characterized by high expression of contractile proteins to synthetic one that is characterized by low expression of contractile proteins and high rate of protein synthesis. On the other hand, apoptosis of vascular smooth muscle cells may cause the loss of smooth muscle cell layer form arterial wall and destabilization of atherosclerotic lesion. The aim of this project is to elucidate the role of mitogen-activated protein kinases (MAP kinases), especially c-Jun N-terminal kinase (JNK), in phenotypic modulation and apoptosis of vascular smooth muscle cells. [ Results ] We established highly differentiated vascular smooth muscle cell culture system as a model system. Platelet-derived growth factor (PDGF) that initiates atheros … More clerotic change preferentially activated ERK family of MAP kinases, whereas oxidative stress by hydrogen peroxide preferentially activated JNK, suggesting different MAP kinase subfamily are mediating intracellular signaling in response to different extracellular stimuli. Both PDGF and hydrogen peroxide caused dedifferentiation of vascular smooth muscle cells in culture. In addition, hydrogen peroxide also caused apoptotic cell death. We made adenoviral vectors encoding dominant negative and wild type JNK, dominant negative and constitutively active SEK1 and MKK7, the upstream regulator of JNK pathway. These adenoviral vectors successfully transduced almost 100 % of vascular smooth muscle cells in culture. Expression of active SEK1 caused dedifferentiation of vascular smooth muscle cells partly mimicking the effect of oxidative stress. We also found that JNK pathway plays a central role in apoptosis of adult cardiac myocytes in culture. We identified a group of genes that are regulated under the control of JNK pathway by transcriptome analyses using DNA microarray. Less