The prevalent distribution of atherosclerotic lesions in the curvature and branches of arterial trees demonstrates the critical role of flow patterns in predisposing the arterial wall to atherosclerosis. Steady flows with a high magnitude of shear stress, the tangential component of hemodynamic forces acting on the endothelium, constitute the waveform of atheroprotective flow. In contrast, flow patterns with a low magnitude of shear stress, oscillation, and reverse flow, are atheroprone. Flow channels have been used as in vitro model systems to demonstrate that shear stress regulates the expression of genes involved in vascular functions. In investigating the mechanotransduction mechanisms, we recently found that AMP-activated protein kinase (AMPK) is modulated by shear stress in vascular endothelial cells (ECs). Moreover, Kr?ppel-like factor 2 (KLF2), a zinc finger transcription factor integrating multiple endothelial functions, is regulated via AMPK in response to shear stress. We thus hypothesize that atheroprotective flow modulates the activity of AMPKK [i.e., calmodulin-dependent protein kinase kinase (CaMKK) and LKB1], which in turn activates AMPK. In addition to rapidly activating eNOS, AMPK augments the transcriptional activation of the klf2 gene to benefit the EC-dependent vascular functions. The activated AMPK-KLF2 would also contribute to the atheroprotective effect of flow. To test our hypothesis, three Specific Aims are proposed.
Specific Aim 1 will dissect the critical shear stress parameters associated with the atheroprotective flow that activates the AMPKK-AMPK cascade in ECs.
Specific Aim 2 will elucidate the molecular mechanism by which AMPK regulates the transcriptional activation of KLF2, which in turn modulates KLF2-targeted genes.
Specific Aim 3 will investigate the role of flow-activated AMPK and KLF2 in vascular tone and atheroprotection. Specifically, we will assess the EC-dependent vessel dilation and NO bioavailability in AMPK knockout (ampk-/-) mice. Further, ampk-/- mice will be crossbred with apoE-/- mice. Atherosclerotic lesions are expected to be enhanced in these double knockout mice, as compared with the apoE-/- littermates.
Aimi ng at studying post-translational and transcriptional regulation by AMPK in ECs exposed to shear stress, we hope this research will establish a framework to further understand the mechano and molecular basis of EC biology regulated by flow.
Atherosclerosis shows a focal pattern of distribution, which is mainly contributed by the distinct flow patterns depending on the locations in the arterial tree. The studies in this proposal address questions regarding the mechano and molecular basis of atheroprotective versus atheroprone flows in modulating the vascular endothelial biology. The proposal will significantly increase our understanding of mechanisms by which blood flow patterns interplay with hyperlipidemia in atherogenesis, which are likely to contribute to novel therapies for its prevention and/or treatment.
|Chen, Zhen; Martin, Marcy; Li, Zhao et al. (2014) Endothelial dysfunction: the role of sterol regulatory element-binding protein-induced NOD-like receptor family pyrin domain-containing protein 3 inflammasome in atherosclerosis. Curr Opin Lipidol 25:339-49|
|Gongol, Brendan; Marin, Traci; Peng, I-Chen et al. (2013) AMPK*2 exerts its anti-inflammatory effects through PARP-1 and Bcl-6. Proc Natl Acad Sci U S A 110:3161-6|
|Koo, Andrew; Dewey Jr, C Forbes; Garcia-Cardena, Guillermo (2013) Hemodynamic shear stress characteristic of atherosclerosis-resistant regions promotes glycocalyx formation in cultured endothelial cells. Am J Physiol Cell Physiol 304:C137-46|
|Marin, Traci; Gongol, Brendan; Chen, Zhen et al. (2013) Mechanosensitive microRNAs-role in endothelial responses to shear stress and redox state. Free Radic Biol Med 64:61-8|
|Zhou, Jing; Li, Yi-Shuan; Nguyen, Phu et al. (2013) Regulation of vascular smooth muscle cell turnover by endothelial cell-secreted microRNA-126: role of shear stress. Circ Res 113:40-51|
|Xiao, Han; Lu, Min; Lin, Ting Yang et al. (2013) Sterol regulatory element binding protein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic-induced atherosclerosis susceptibility. Circulation 128:632-42|
|He, Ming; Liang, Xiao; He, Lan et al. (2013) Endothelial dysfunction in rheumatoid arthritis: the role of monocyte chemotactic protein-1-induced protein. Arterioscler Thromb Vasc Biol 33:1384-91|
|Chen, Zhen; Lai, Tsung-Ching; Jan, Yi-Hua et al. (2013) Hypoxia-responsive miRNAs target argonaute 1 to promote angiogenesis. J Clin Invest 123:1057-67|
|Peng, I-Chen; Chen, Zhen; Sun, Wei et al. (2012) Glucagon regulates ACC activity in adipocytes through the CAMKK?/AMPK pathway. Am J Physiol Endocrinol Metab 302:E1560-8|
|Wu, Wei; Xiao, Han; Laguna-Fernandez, Andrés et al. (2011) Flow-Dependent Regulation of Kruppel-Like Factor 2 Is Mediated by MicroRNA-92a. Circulation 124:633-41|
Showing the most recent 10 out of 18 publications