San Martin cardiovascular lab

The Emory University San Martin Lab is a Division of Cardiology lab within the Emory Department of Medicine.

The focus of the San Martin research is on understanding smooth muscle cell (VSMC) signaling pathways and phenotypic modulation during normal physiological conditions and during diseases.  We are particularly interested in the participation of reactive oxygen species (ROS) produced by the NADPH oxidase (Nox) family of enzymes as mediators of a wider repertoire of cellular responses such as: cytoskeleton reorganization and gene expression.

Research Overview

Reactive oxygen species (ROS) play a significant role in the development of various cardiovascular diseases such as hypertension, atherosclerosis and restenosis after angioplasty. Within the vessel wall, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases are the main source of O2•− and H2O2 production. They can produce ROS within different compartments. More importantly, these ROS are involved in many signaling pathways during normal physiology and during cardiovascular diseases.

Our laboratory studies the molecular pathways targeted by ROS in the regulation of VSMC cytoskeletal reorganization and migration. We have previously shown that in order to migrate in response to PDGF, VSMCs require the activation of the specific phosphatase, Slingshot 1L (SSH1L), which dephosphorylates cofilin and therefore controls the first step in migration, lamellipodia formation. Using a unique Nox1 transgenic animal model, we identified SSH1L activation as a redox-regulated process that involves the oxidation of its inhibitory binding partner 14-3-3.

Because cells in the cardiovascular system are permanently subjected to mechanical forces created by the beating heart, an additional interest of our lab is to study how the cells sense mechanical stimulation and the role of these biomechanical forces on vascular inflammation and remodeling.  We have focused on Nox4 as one of the key protein that sense biomechanical force by linking the cell cytoskeleton to the extracellular matrix. Indeed, Nox4 has been shown to be important for actin cytoskeleton and focal adhesion maintenance, another interest of our lab has been to identify the signaling pathways that Nox4 uses to regulate the cytoskeleton.  Currently, we are studying the role of the FA resident protein Hic5 and chaperon protein Hsp27 in Nox4-mediated focal adhesion maintenance. Our laboratory has demonstrated that treatment with factor TGF-β increases Hic5 and Hsp27 and induces their co-localization to stress fibers and the cytosol via Nox4. More importantly, we found that this Hic5/Hsp27 interaction is required for trafficking of Hic5 to FAs. Taken together, our work identifies Hic5 as a novel effector of Nox4 and supports the idea that Nox4 mediates TGF-β-induced FA maturation by upregulation and interaction of Hic5 and Hsp27 that specifically targets Hic5 to FA.

Team Members

San Martin

Alejandra San Martin, PI

Lab Staff

  • Alejandra Valdivia, PhD, Postdoctoral fellow
    Alejandra is a Biologist from Universidad Catolica de Chile and PhD in Biomedical Sciences from the Universidad de Chile. Her main research interest is to study how Rho family of GTPases could affect cytoskeleton dynamics of vascular smooth muscle cells during normal and pathological conditions.
  • Kely Sheldon, Postdoctoral fellow
  • Gloria Torres, DVM PhD, Postdoctoral fellow
    Gloria is a DVM and PhD in Biochemistry from the Universidad de Chile. To obtain her DVM degree, she investigated the effect of some traditional drugs like aspirin could improve the immune response in Chagas disease. Then, to obtain her PhD degree, she studied the changes in mitochondrial dynamics and function caused by an analog of glucagon in vascular smooth muscle cell. Now, in San Martin's lab the team is studying how a protein that regulates cytoskeleton dynamics could affect mitochondrial dynamics-function and change cell metabolism of vascular smooth muscle cell.
  • Holly Williams, postdoctoral fellow

Lab Alumni

  • Kelly Clause, PhD
  • Charity Duran, PhD
  • Isabel Fernandez, BS
  • Hope Gole, PhD
  • Mithu Maheswaranathan, BS
  • Marcelo Montenegro, PhD
  • Kiran Verma, MS
  • Zhen Yang, PhD

Collaborators

Publications

  1. Valdivia A, Duran C, San Martín A. The role of Nox-mediated oxidation in the regulation of cytoskeletal dynamics. Current Pharmaceutical Design. In press.
  2. Sheldon KL, San Martin A. Role of subplasmalemmal mitochondria in Angiotensin II–Mediated Contraction. Circ Res. 2015. In press.
  3. Montenegro MF, Valdivia A, Smolensky A, Verma K, Taylor WR, San Martín A. Nox4-dependent activation of cofilin mediates VSMC reorientation in response to cyclic stretching. Free Radical Biology and Medicine. 19;85:288-294. 2015.PMID: 25998423.
  4. Fernandez I, Martin-Garrido A, Clempus RE, Seidel-Rogol B, Amanso A, Lassègue B, Griendling KK, San Martín A. Hic-5 and Hsp27 are downstream effectors of Nox4 in TGF-β- stimulated focal adhesions in smooth muscle. Atherosclerosis Thrombosis and Vascular Biology; 35(5):1198-206.2015 PMID: 25814672
  5. Duran C, San Martín A. Do endothelial cells eat tryptophan to die? Circ Res. 2014 Jan 31;114(3):406-8. PMID: 24481839
  6. San Martín A, Griendling K. NADPH Oxidases: Progress and Opportunities. Antioxid Redox Signal. 2014. Jun 10;20(17):2692-4. doi: 10.1089/ars.2014.5947.
  7. Martin-Garrido A, Williams HC, Lee M, Seidel-Rogol B, Ci X, Dong JT,
  8. Lassègue B, San Martín A, Griendling KK. Transforming growth factor β inhibits platelet derived growth factor-induced vascular smooth muscle cell proliferation via Akt-independent, Smad-mediated cyclin D1 downregulation. PLoSOne.; 8(11):e79657. PMID: 24236150.
  9. Williams HC, San Martín A, Adamo CM, Seidel-Rogol B, Pounkova L, Datla SR, Lassègue B, Bear JE, Griendling K. Role of Coronin 1B in PDGF-Induced Migration of Vascular Smooth Muscle Cells. Circ Res. 2012; 111(1):56-65. PMID: 22619279
  10. Lassègue B*, San Martín A* and Griendling KK.  Biochemistry, Physiology and Pathophysiology of NADPH Oxidases in the Cardiovascular System.  Circ Res 2012; 110(10):1364-90.PMID: 22581922 (*Authors contributed equally)
  11. Maheswaranathan M, Gole H, Fernandez I, Lassegue B, Griendling KK, San Martín A.  PDGF regulates slingshot phosphatase activity via Nox1-dependent auto-dephosphorylation of serine 834 in vascular smooth muscle cells. Journal of Biological Chemistry. 2011; 286(41):35430-7.
  12. San Martín A, Griendling KK. Redox control of vascular smooth muscle migration. Antioxidants and Redox Signaling 2010;12(5):625-40.
  13. Martin-Garrido A, Brown D, Lyle AN, Dikalova A, San Martín A, Griendling KK. NADPH oxidase 4 mediates TGF-β-induced smooth muscle α-actin via p38MAPK and serum response factor.  Free Radic Biol Med 2010, 15;50(2):354-62.
  14. Engberding N, San Martín A, Lassègue B, Griendling KK. Insulin-like growth factor-1 receptor expression masks the anti-inflammatory capacity of insulin in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2009; 29:408-415.
  15. Lee MY, San Martín A, Mehta P, Dikalova A, Martin Garrido A, Krause KH, Banfi B, Lambeth DJ, Lassègue B, Griendling KK. Contribution of Vascular Smooth Muscle NADPH oxidase 1 (Nox1) to Injury-induced Neointimal Formation. Arterioscler Thromb Vasc Biol. 2009; 29(4):480-487.
  16. San Martín A, Lee MY, Holly Williams, Lassègue B, Griendling KK. Dual regulation of cofilin activity by LIMK and slingshot 1L phosphatase controls PDGF-induced migration of human aortic smooth muscle cells. Circulation Research 2008; 102: 432-438
  17. San Martín A, Foncea R, Laurindo RF, Ebensperger R, Griendling KK, Leighton F. Nox1-based NADPH oxidase-derived superoxide is required for VSMC activation by advanced glycation end-products. Free Radical Biology and Medicine 2007; 42: 1671–1679.
  18. San Martín A, Du P, Dikalova A, Lassegue B, Aleman M, Gongora MC, Brown K, Joseph G, Harrison DG, Taylor WR, Jo H, Griendling KK.  Reactive oxygen species-selective regulation of aortic inflammatory gene expression in type 2 diabetes.   American Journal of Physiology, Heart and Circulatory Physiology 2007; 292: H2073-H2082.

Contact Us

If you have any questions, please contact us at 404-727-1738 or via email asanmartin@emory.edu

Emory University School of Medicine 
Department of Medicine, Cardiology Division 
307 Woodruff Memorial Building 
1639 Pierce Drive
Atlanta, GA 30322