Cell and tissues are subjected to different types of mechanical stress. Hypertension is a pathological state in which the increase in pressure induces enhanced mechanical forces within the vessel wall. One of the consequences of hypertension is the induction of inflammatory gene expression in the vasculature. Although inflammation may facilitate hypertension-related cardiovascular complications, the molecular pathways that result in hypertension-induced inflammation are incompletely described vascular smooth muscle cells (VSMCs), a main component of the vessel wall, respond to biomechanical forces initiated by hemodynamic changes and undergo phenotypic modulation. Indeed, this modulation results in reorientation of the cell body, which has been proposed as one mechanism to counteract the strain. Reactive oxygen species (ROS) play important roles as signaling molecules in all types of vascular cells. One main source of ROS in the vasculature is Nox4, which is found in focal adhesions (FAs), the sites of engagement of the cell to the extracellular substrate. We have shown that Slingshot 1L (SSH1L) phosphatase, which dephosphorylates and thus activates its substrate, the actin binding protein cofilin, plays a key role in the control of PDGF-induced lamellipodia formation and VSMC migration. Now, we have exciting preliminary data indicating that SSH1L-mediated cofilin activation is required for cell reorientation and, most significantly, for the regulation of inflammatory gene expression when VSMC are subjected to mechanical stress. We hypothesize that in response to mechanical stress, integrins activate the Nox4-based NADPH oxidase to produce H2O2 that induces SSH1IL-mediated cofilin activation within the FA, and that activated cofilin is required for cell reorientation and translocates to the nucleus where it regulates the transcription of inflammatory genes. During this grant period we aim to: 1. Identify the mechanism of mechanical stretch-induced SSH1L/cofilin activation and its role in cell reorientation in VSMC, 2. Define the mechanism of cofilin nuclear translocation and its role in regulating the gene expression and 3. Determine the role of the Nox4/cofilin pathway in attenuating hypertension-induced vascular inflammation in vivo. Experiments described in this application will increase our understanding about how cells sense mechanical stimuli and the consequences of such stimuli on cell phenotype, providing sufficient proof-of principle to support the identification of new therapeutic targets.
Vascular smooth muscle cells (VSMCs), a main component of the vessel wall are subjected to pulsatile strain. Hypertension, where cells are chronically subjected to increased strain, is a risk factor for cardiovascular diseases in part due to an increased inflammation in the vascular tissue. This project will investigate the role of the actin binding protein cofilin in mediating cell reorientation and inhibiting inflammatory gene expression in response to mechanical stress in VSMCs. Understanding the mechanism underlying the vessel adaptation to mechanical stimulus may lead to development of therapeutic treatments that target important events in disease initiation. !
|Williams, Holly C; Ma, Jing; Weiss, Daiana et al. (2018) The cofilin phosphatase slingshot homolog 1 restrains angiotensin II-induced vascular hypertrophy and fibrosis in vivo. Lab Invest :|
|Yeligar, Samantha M; Kang, Bum-Yong; Bijli, Kaiser M et al. (2018) PPAR? Regulates Mitochondrial Structure and Function and Human Pulmonary Artery Smooth Muscle Cell Proliferation. Am J Respir Cell Mol Biol 58:648-657|
|Paredes, Felipe; Sheldon, Kely; Lassègue, Bernard et al. (2018) Poldip2 is an oxygen-sensitive protein that controls PDH and ?KGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer. Proc Natl Acad Sci U S A 115:1789-1794|
|Paredes, Felipe; Parra, Valentina; Torrealba, Natalia et al. (2016) HERPUD1 protects against oxidative stress-induced apoptosis through downregulation of the inositol 1,4,5-trisphosphate receptor. Free Radic Biol Med 90:206-18|
|Torres, Gloria; Morales, Pablo E; García-Miguel, Marina et al. (2016) Glucagon-like peptide-1 inhibits vascular smooth muscle cell dedifferentiation through mitochondrial dynamics regulation. Biochem Pharmacol 104:52-61|
|Lee, Minyoung; San Martín, Alejandra; Valdivia, Alejandra et al. (2016) Redox-Sensitive Regulation of Myocardin-Related Transcription Factor (MRTF-A) Phosphorylation via Palladin in Vascular Smooth Muscle Cell Differentiation Marker Gene Expression. PLoS One 11:e0153199|
|Valdivia, Alejandra; Duran, Charity; San Martin, Alejandra (2015) The role of Nox-mediated oxidation in the regulation of cytoskeletal dynamics. Curr Pharm Des 21:6009-22|
|Montenegro, Marcelo F; Valdivia, Alejandra; Smolensky, Alexander et al. (2015) Nox4-dependent activation of cofilin mediates VSMC reorientation in response to cyclic stretching. Free Radic Biol Med 85:288-94|
|Fernandez, Isabel; Martin-Garrido, Abel; Zhou, Dennis W et al. (2015) Hic-5 Mediates TGF?-Induced Adhesion in Vascular Smooth Muscle Cells by a Nox4-Dependent Mechanism. Arterioscler Thromb Vasc Biol 35:1198-206|
|Sheldon, Kely L; San Martín, Alejandra (2015) Role of Subplasmalemmal Mitochondria in Angiotensin II-Mediated Contraction. Circ Res 117:984-6|
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