ReviewBiomechanical-stress-induced Signaling and Gene Expression in the Development of Arteriosclerosis
Section snippets
MAPK Signal Pathways
Cells respond to extracellular stimuli by activating signal transduction pathways, which culminate in changes in gene expression. A critical component of eukaryotic signal transduction is the activation of protein kinases that phosphorylate a host of cellular substrates, including transcription factors controlling the induction of various genes. In mammalian cells, MAPKs are thought to play a pivotal role in transmitting transmembrane signals required for cell proliferation, differentiation and
Biomechanical-stress-induced Cell Death
Apoptosis of SMCs and macrophages has recently been demonstrated in atherosclerotic lesions of humans as well as animal models (Kockx 1998). Interestingly, isolated SMCs from human atherosclerotic plaques were shown to have a higher propensity for both spontaneous and induced apoptosis compared with SMCs from normal vessels (Bennett et al. 1995). On the other hand, activation of MEKK1, a SAPK/JNK upstream kinase, -SAPK/JNK pathways is implicated in the initiation of apoptosis in other cell
Biomechanical-stress-induced Gene Expression Related to Inflammation
Atherosclerosis is an inflammatory disease characterized by mononuclear cell infiltration, including monocytes/macrophages, T lymphocytes, B cells, mast cells and dentritic cells Libby and Hansson 1991, Wick et al. 1997, Ross 1999. Atherosclerotic lesions display many characteristic markers of inflammation, for example, adhesion molecule overexpression and pro-inflammatory cytokine production (Libby and Hansson 1991). Moreover, inflammatory and immune responses in the development of transplant
Biomechanical-stress-activated PDGF-MAPK Pathways Leading to SMC Proliferation
It has been established that mechanical stress stimulates DNA synthesis and proliferation of in vitro cultured SMCs (Wilson et al. 1993). Hypertension increases mechanical force on the arterial wall up to 30%, resulting in marked alterations in signal transductions and gene expression in SMCs, which contribute to matrix protein synthesis, cell proliferation and differentiation. Large arteries, such as the aorta, coronary and carotid arteries, undergo adaptation or remodeling in response to
Conclusions
During the last several years, large amounts of data concerning signal transductions in mammalian cells have been obtained, and MAPK-mediated signal pathways have been thoroughly studied. Focusing on the vasculature, our observations, together with others, demonstrated that mechanical-stress-stimulated growth factor receptor-MAPK pathways play a crucial role in the pathogenesis of arteriosclerosis. Thus, a new model of biomechanical-stress hypothesis has been formulated, that is, that
Acknowledgements
I am grateful to Dr. Georg Wick for his continuous support. I thank Drs. Manuel Mayr, Chaohong Li, Hermann Dietrich and Yanhua Hu, who, together with many other collaborators, played a critical role in the work summarized in this review. This work was supported by grants P13099-BIO and P12568-MED from the Austrian Science Fund and P7919 from the Jubiläumsfonds of the Austrian National Bank.
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