Chen Yan, Ph.D.

Chen Yan

Chen Yan , Ph.D.
Assistant Professor

Chen_Yan@urmc.rochester.edu

Primary Appointment:
Department of Medicine in the
Aab Cardiovascular Research Institute

GEBS Cluster Affiliation:
CVS-Cardivascular Sciences
CMM-Cellular and Molecular Basis of Medicine


Aab Cardiovascular Research Institute of the University of Rochester School of Medicine and Dentistry
211 Bailey Road
Rm. A210D
West Henrietta, NY 14586

Phone: (585) 276-9792
Fax: (585) 276-9830
Research
  • Regulation and function of cyclic nucleotide phosphodiesterases in the cardiovascular system.
Background

Dr. Chen Yan received her Bachelor of Science degree in Biochemistry in 1983 and Master’s degree in Human/Medical Genetics from the Fudan University in 1986. She received her Ph.D. degree in molecular pharmacology from the University of Washington (UW), Seattle in 1996 and performed her postdoctoral training in molecular cardiology, also at UW. She was recruited to the University of Rochester as a Research Assistant Professor in December 1998. She currently is a assistant professor.

Research Overview

General Research Interests: Regulation and function of cyclic nucleotide phosphodiesterases in the cardiovascular system. Second messenger cyclic nucleotides (cAMP and cGMP) regulate many signaling pathways in the cardiovascular system. For example, the vascular tone, smooth muscle cell growth, and cardiac muscle contractility are all regulated by cyclic nucleotide signaling. We are interested in phosphodiesterases (PDEs), the enzymes that break down cyclic nucleotides and thus control the amplitude, duration, and compartmentalization of cyclic nucleotide signaling in the cell. It has become increasingly clear that cyclic nucleotide degradation by PDEs is not a constitutive function of the cell, but rather a highly regulated one controlled by different mechanisms in different physiological and pathological circumstances. PDE regulation and function is further complicated by the fact that there are more than 50 individual PDEs belonging to 11 different PDE families, yet our understanding of the physiological function of each PDE is far from complete. PDEs have been demonstrated to be good pharmacological targets for therapeutic agents due to the presence of multiple structurally different, tissue-specific, differentially regulated, and functionally distinct isozymes. Several drugs, such as Viagra, have been shown to have unique specific effects via selectively inhibit individual PDE isozymes. Our focus has been on determining the regulation and function of individual PDE isozymes in cardiovascular diseases such as hypertension, atherosclerosis, heart failure, and cardiovascular inflammatory diseases. Ongoing and future studies using in vitro and in vivo approaches will focus on the various roles of PDEs in cardiovascular physiology and pathology, which may provide new therapeutic information for tissue specific interventions in cardiovascular diseases.

Recent Publications

  1. Yan C, Luo H, Lee J-D, Abe J, and Berk BC (2001). Molecular Cloning of Mouse ERK5/BMK1 Splice Variants and Characterization of ERK5 Functional Domains. J. Biol. Chem. 276:10870-10878.
  2. Cavanaugh JE, Ham J, Hetman M, Poser S, Yan C, and Xia Z (2001). Differentail Regulation of Mitogen-Activated Protein Kinases ERK1/2 and ERK5 by Neurotrophins, Neuronal Activity, and cAMP in Neurons. J. Neuroscience 21(2):434-443.
  3. Berk BC, Abe J, Wang M, Surapisitchat J., and Yan C. (2001). Endothelial atheroprotective and anti-inflammatory mechanisms. Ann. N Y Acad. Sci. 947:93-109.
  4. Yan C, Zhao AZ, Sonnenburg WK, and Beavo JA (2001). Stage and Cell–Specific Expression of CaM-PDEs in Mouse Testis. Biology of Reproduction, 64:1746-1754.
  5. Surapisitcht J, Hoefen JR, Pi X, Yoshizumi M, Yan C, Berk BC, (2001). Fluid shear stress inhibits TNF-a activation of JNK but not ERK1/2 or p38 in human umbilical vein endothelial cells : inhibitory crosstalk among MAPK family members. Proc. Nat. Acad. Sci. USA 98: 6476-6481.
  6. Kim D-S, Rebulkin S, Pi X, Zhang C, Munzel T, Beavo JA, Berk BC, Yan C. (2001). Upregulation of phosphodiestrase 1A1 expression is associated with the development of nitrate tolerance. Circulation. 104:2338-2343.

    Editorial Commentary: Parker JD, Gori (2001). Tolerance to the Organic Nitrates, New Ideas, New Mechanisms, Continued Mystery. Circulation 104:2263-2265.

  7. Che W, Abe J, Yoshizumi M, Huang Q-H, Glassman M, Ohta S, Melaragno MG, Poppa V, Yan C, Lerner-Marmarosh N, Zhang C, Wu Y, Arlinhaus R, Berk BC (2001). p160 Bcr mediates platelet-derived growth factor activation of extracellular signal-regulated kinase in vascular smooth muscle cells. Circulation. 104:1399-1406.
  8. Takeishi Y, Hang Q, Wang T, Glassman M, Yoshizumi M, Baines CP, Lee J-D, Kawakatsu H, Che W, Lerner-Marmarosh N, Zhang C, Yan C, Ohta S, Walsh RA, Berk BC, and Abe J. (2001). Src family kinase and adenosine differentially regulate multiple MAP kinases in ischemic myocardium: Modulation of MAP kinases activation by ischemic preconditioning. J. Mol. Cell. Cardiol. 33:1989-2005.
  9. Berk BC, Surapisitchat J, Yoshizumi M, Yan C. Hoefen R, and Abe J (2001). Atheroprotective mechanisms of fluid shear stress: nitric oxide independent inhibition of signal transduction mediated by inflammatory cytokines. In Vascular Endothelium-Source and Target of Inflammatory Mediators. Edited by J. D. Catravas, A. D. Callow, U. S. Ryan, and M. Simionescu. IOS Press. p115-125.
  10. Surapisitchat J, Yan C, and Berk BC (2001). Flow-mediated Activation of MAP Kinase. In Vascular Protection: Molecular Mechanisms, Novel Therapeutic Principles, and Clinical Application. Edited by Gabor M. Rubanyi, Victor J. Dzau, and John P. Cooke. P167-164.
  11. Berk BC, Wang M., Yan C., Surapisitchat J. and Hoefen R. (2002). Atheroprotective Mechanisms Activated by Fluid Shear Stress in Endothelial Cells. Drug News Perspect 15: 1-7.
  12. Pi X.*, Yan C*, Kim D-S, Chen J, and Berk BC (2002). Differential expression of genes from nitrate tolerant rat aorta. Journal of Vascular Research. 39:304-310.
    (* Contributed equally to this manuscript).
  13. Frame MD, Fox RJ, Kim D-S, Mohan A, Berk BC, and Yan C. (2002). Diminished arteriolar responses in nitrate tolerance involve ROS and angiotensin II. Am. J. Physiol. 282: H2377-H2385.
  14. Che W, Lerner-Marmarosh N, Huang Q, Osawa M, Ohta S, Yoshizumi M, Glassman M, Lee J-D, Yan C, Berk BC, and Abe J. (2002). Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: Role of Gab1 and MEKK3 in TNF-a induced c-Jun and NF-kB activation and adhesion molecule expression. Circulation Research, 90:1222-1230.
  15. Huang Q, Lerner-Marmarosh N, Che W, Ohta S, Osawa M, Yoshizumi M, Glassman M, Yan C, Berk BC, and Abe J. (2002). The novel role of C-terminal region of SHP-2 : Involvement of Gab1 and SHP-2 phosphatase activity in Elk-1 activation. J. Biol. Chem, 277(32): 29330-29341.
  16. Tai L, Okada M, Abe J, Yan C, and Berk BC (2002). Fluid shear stress activates Pyk2 via a reactive oxygen species dependent pathway. Arterioscler. Thromb. Vasc. Biol. 22: 1790-1796.
  17. Cameron SJ, Malik, Lerner-Marmarosh N, Yan C, Akaike M, Lee J-D, Abe J, and Yang J, (2003). Regulation of EGF-induced connexin 43 gap junction communication by BMK1/ERK5 but not ERK1/2 kinase activation. J. Biol. Chem. 278(20):18682-8.
  18. Yan C., Kim D, Aizawa T, and Berk BC (2003). Functional interplay between angiotensin II and nitric oxide: cyclic GMP as a key mediator. Arterioscler. Thromb. Vasc. Biol. 23: 26-36.
  19. Yin G., Yan C and Berk BC (2003). Angiotensin II signaling pathway mediated by tyrosine kinases. International Journal of Biochemistry and Cell Biology 35:780-783.
  20. Rybalkin S, Yan C, Bornfeldt KE, and Beavo JA (2003). Cyclic GMP Phosphodiesterases and Regulation of Smooth Muscle Function. Circulation Research 93(4):280-91.
  21. Aizawa T, Wei H, Miano JM, Abe J, Berk BC, and Yan C. (2003). Anti-inflammatory effects of NO/cGMP are mediated by PDE3 inhibition in vascular smooth muscle cell. Circulation Research, 93: 406-413.
  22. Lerner-Marmarosh N, Yoshizumi M, Che W, Surapisitchat J, Kawakatsu H, Akaike M, Ding B, Huang Q, Yan C, Berk BC, Abe J (2003). Inhibition of Tumor Necrosis Factor-{alpha}-Induced SHP-2 Phosphatase Activity by Shear Stress. A Mechanism to Reduce Endothelial Inflammation. Arterioscler Thromb Vasc Biol. 23: 1775-1781.
  23. Haendeler J, Yin Y, Hojo Y, Saito Y, Melaragno M, Yan C, Heller M, Aebersold R, and Berk BC (2003). GIT1 Mediates Src-dependent Activation of PLCr by Angiotensin II and EGF. J. Biol. Chem. 278:49936-44.
  24. Yin G, Haendeler J, Yan C, Berk BC (2004). GIT1 functions as a scaffold for MEK1-ERK1/2 activation by angiotensin II and EGF. Mol. Cell. Biol., 24: 875-85.
  25. Pi X, Yan C, and Berk BC (2004). Big Mitogen-activated protein kinase (BMK1)/ERK5 protects endothelial cells from apoptosis. Circulation Research, 94: 362-9.
  26. Zheng Q, Yin G, Yan C, Cavet M, and Berk BC (2004). 14-3-3beta binds to big mitogen activated protein kinase 1 (BMK1/ERK5) and regulates BMK1 function. J. Biol. Chem. 279: 8787-91.
  27. Cameron SJ, Itoh S, Baines CP, Zhang C, Ohta S, Che W, Glassman M, Lee JD, Yan C, Yang J, and Abe JI (2004). Activation of big MAP kinase 1, (BMK1/ERK5) inhibits cardiac injury, after myocardial ischemia and reperfusion. FEBS Lett 566: 255-260.
  28. Osawa M, Itoh S, Ohta S, Huang Q, Berk BC, Marmarosh NL, Che W, Ding B, Yan C, Abe JI (2004). ERK1/2 associates with the c-Met binding domain of Gab1: Role in ERK1/2 and Egr-1 nuclear accumulation. J Biol. Chem. 79(28): 29691-9.
  29. Melaragno MG, Cavet ME, Yan C, Tai L, Jin Z, Haendeler J, Berk BC (2004). Gas6 inhibits apoptosis in vascular smooth muscle: role of Axl kinase and Akt. J. Mol. Cell. Cardiol. 37:881-887.
  30. Akaike M, Wei C, Lerner-Marmarosh N, Osawa S, Bo D, Berk BC, Yan C, Abe J (2004). Hinge-helix1 region of PPARg1 mediates interaction with ERK5 and PPARg1 transcriptional activation: Involvement in flow-induced PPARg activation in endothelial cells. Mol Cell Biol. 24: 8691-704.
  31. Kim D, Aizawa T, Wei H, Pi X, Rybalkin SD, Berk BC, Yan C (2005). Angiotensin II Increases Phosphodiesterase 5A Expression in Vascular Smooth Muscle Cells: A Mechanism by Which Angiotensin II Antagonizes cGMP signaling. J. Mol. Cell. Cardiol. 38: 175-184.
  32. Ding B, Abe J, Wei H, Huang Q, Walsh RA, Molina, CA, Zhao A, Sadoshima J, Blaxall BC, Berk BC, Yan C. (2005). Functional Role of Phosphodiesterase 3 in Cardiomyocyte Apoptosis: Implication in Heart Failure. Circulation. 111, 2469-76.
  33. Itoh S, Ding B, Bains CP, Wang N, Takeishi Y, Jalili T, King GL, Walsh RA, Yan C, Abe JI. (2005). Role of p90 ribosomal S6 kinase (p90RSK) in reactive oxygen species and PKCbeta -mediated cardiac troponin I phosphorylation. J Biol Chem. 280:24135-42.
  34. Pi X, Garin G, Xie L, Zheng Q, Wei H, Abe JI, Yan C, Berk BC. (2005). BMK1/ERK5 Is a Novel Regulator of Angiogenesis by Destabilizing Hypoxia Inducible Factor 1{alpha}. Circulation Research 96: 1145-51.
  35. Yin G, Zheng Q, Yan C, Berk, BC. (2005). GIT1 is a scaffold for ERK1/2 activation in focal adhesion. J. Biol. Chem. 280:27705-12.
  36. Vasta V, Sonnenburg WK, Yan C, Sodeling SH, Shimizu-Albergine M, Beavo JA. (2005). Identification of a New Cycic Nucleotide Phosphodiesterase Expressed in Mouse Sperm. Biol. Reprod. 73 (4): 598-609.
  37. Ding B, Abe JI, Wei H, Che, W, Aizawa, T, Liu W, Molina CA, Sadoshima, JI, Blaxall BC, Berk BC, Yan C (2005). A positive Feedback Loop of Phosphodiesterase 3 (PDE3) and Inducible cAMP Early Repressor (ICER) Leads to Cardiomyocyte Apoptosis. PNAS. 102 (41): 14771-14776.
    Editorial Commentary:
    Brunton LL (2005). A positive feedback loop contributes to the deleterious effects of antiotensin. PNAS. 102:14483-14484.
  38. Shen W, Gao P, Che Z, Ji K, Yin M, Yan C, Berk BC, and Zhu D. (2005). NAD(P)H oxidase-derived reactive oxygen species regulate angiotensin-II induced adventitial fibroblast phenotypic differentiation. Biochemical and Biophysical Research Communication 339:337-343.
  39. Yan C. (2005). Determination of Ca2+/Calmodulin-Stimulated Phosphodiesterase Activity in Intact Cells. Methods Mol. Biol. 307:85-92.
  40. Qin F, Patel R, Yan C, Liu W (2006). NADPH oxidase is involved in angiotensin II-induced apoptosis in H9C2 cardiac cells: Effects of apocynin. Free Radical Biology and Medicine 40:236-246.
  41. Qin F, Yan C, Patel R, Liu W, Dong E (2006). Vitamins C and E attenuate apoptosis, beta-adrenergic receptor desensitization and sarcoplasmic reticular Ca2+ ATPase downregulation after myocardial infarction. Free Radical Biology and Medicine 40:1827-1842.
  42. Itoh S, Ding B, Shishido T, Lerner-Marmarosh N, Wang N, Maekawa N, Berk BC, Takeishi Y, Yan C, Blaxall BC, Abe J (2006). Role of p90 ribosome s6 kinase (p90RSK)-mediated pro-renin converting enzyme (PRECE) in ischemic and diabetic myocardium. Circulation 113: 1787-1798.
  43. Nagel DJ, Aizawa T, Jeon K, Liu W, Mohan A, Wei H, Miano JM, Florio VA, Gao P, Korshunov VA, Berk BC, and Yan C (2006). Role of Nuclear Ca2+/calmodulin-stimulated Phosphodiesterase 1A in Vascular Smooth Muscle Cell Growth and Survival. Circulation Research 98: 777-784.

    Editorial Commentary: Parker JD, Gori (2001). Tolerance to the Organic Nitrates, New Ideas, New Mechanisms, Continued Mystery. Circulation 104:2263-2265.

  44. Woo CH , Massett MP, Shishido T, Itoh S, Ding B, McClain C, Che W, Vulapalli SR, Yan C, Abe JI (2006). ERK5 activation inhibits inflammatory responses via peroxisome proliferators-activated receptor delta (PPARdelta ) stimulation. J. Bio. Chem. 281: 32164-74.
  45. Yan C, Nagel DJ, Jeon K (2006). Regulation and Function of Cyclic Nucleotide Phosphodiesterases in Vascular Smooth Muscle and Vascular Diseases. In Cyclic Nucleotide Phosphodiesterases in Health and Disease. Edited by Joseph Beavo, Sharron Francis, and Miles Houslay. CRC Press. p465-484.
  46. Yan C, Ding B, Shishido T, Woo C-H, Itoh S, Jeon K, Liu W, Xu H, McClain C, Molina CA, Blaxall BC, and Abe JI (2007). Activation of ERK5 reduces cardiac apoptosis and dysfunction via inhibition of a PDE3A-ICER feedback loop. Circulation Research 100(4):510-9.
  47. Ishinaga H, Jono H, Lim JH, Kweon SM, Xu H, Ha UH, Xu H, Koga T, Yan C, Feng XH, Chen LF, Li JD (2007). TGF-beta induces p65 acetylation to enhance bacteria-induced NF-kappaB activation. EMBO J., 26(4):1150-62.
  48. Yan C, Miller C, and Abe JI (2007). Phosphodiesterase 3 (PDE3) and Inducible cAMP Early Repressor (ICER) Regulation in the Heart. Circulation Research 100(4):489-501.
  49. Garin G, Abe J-I, Mohan A, Lu W, Yan C, Newby AC, Rhaman A and Berk BC (2007). Flow antagonizes TNF-a signaling in endothelial cells by inhibiting caspase-dependent PKCzeta cleavage. Accepted by Circulation Research 101 (1): 97-105.
  50. Huang Y, Mikami F, Jono H, Zhang W, Weng X, Koga T, Xu H, Yan C, Kai H, Li JD (2007). Opposing roles of PAK2 and PAK4 in synergistic induction of MUC5AC mucin by bacterium NTHi and EGF. Biochem. Biophys. Res. Commun., 359(3):691-6.
  51. Chen C, Korshunov VA, Massett MP, Yan C, and Berk BC (2007). Impaired vasorelaxation in inbred mice is associated with alterations in both nitric oxide and super oxide pathways. J Vasc Res. 44 (6): 504-512.
  52. Lim JH, Stirling B, Derry J, Koga T, Jono H, Woo CH, Xu H, Bourne P, Ha UH, Ishinaga H, Xu H, Andalibi A, Feng XH, Zhu H, Huang Y, Zhang W, Weng X, Yan C, Yin Z, Briles DE, Davis RJ, Flavell RA, Li JD (2007). Tumor Suppressor CYLD Regulates Acute Lung Injury in Lethal Streptococcus pneumoniae Infections. Immunity. 27(2):349-60.
  53. Surapisitchat J, Jeon K, Yan C, Beavo JA (2007). Differential regulation of endothelial cell permeability by cGMP via phosphodiesterase 2 and 3. Circulation Research. 101:811-

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