Gary K. Owens

Education

  • BS, Pennsylvania State University
  • MS, Pennsylvania State University
  • PhD, Pennsylvania State University
  • Postdoc, University of Washington, Seattle

Primary Appointment

  • Professor, Molecular Physiology and Biological Physics

Contact

Research Interest(s)

Identification of Factors and Mechanisms that Regulate the Stability of Late Stage Atherosclerotic Lesions and the Probability of Thromboembolic Events Including a Heart Attack or Stroke

Research Description

Identification of Factors and Mechanisms that Regulate the Stability of Late Stage Atherosclerotic Lesions and the Probability of Thromboembolic Events Including a Heart Attack or Stroke

Atherothrombosis, resulting from rupture or erosion of unstable atherosclerotic plaques, is the leading cause of death worldwide. However, the mechanisms that regulate the stability of late stage atherosclerotic lesions remain poorly understood. The general dogma based on extensive human histopathology studies is that: 1) plaque composition not size is a critical determinant of late stage lesion stability and the probability of rupture or erosion and a possible heart attack or stroke; 2) plaques containing a large necrotic core, a thin fibrous cap, and large numbers of CD68+ cells relative to Acta2+ cells [presumed to be macrophages (MФ) and smooth muscle cells (SMC) respectively] are more prone to rupture or erosion; and 3) the primary role of the SMC is athero-protective by virtue of them being the primary cell type responsible for formation of a protective fibrous cap.

However, several recent Nature Medicine studies1, 2 by our lab involving simultaneous SMC lineage tracing and SMC-specific knockout (KO) of the stem cell pluripotency genes Oct4 or Klf4, have provided compelling evidence challenging this dogma and showing that SMC play a much greater role in lesion pathogenesis than has been generally appreciated [see our recent review3]. For example, we showed that >80% of SMC-derived cells within advanced lesions of ApoE-/- mice fed a Western diet (WD) for 18 weeks lacked detectable expression of SMC markers such as Acta2 typically used to identify them meaning that previous studies in the field have grossly under-estimated the number of SMC-derived cells within advanced lesions. Moreover, >30% of cells previously identified as MФ within advanced mouse brachiocephalic artery (BCA) lesions and human advanced coronary artery lesions were found to be of SMC not myeloid origin meaning that previous estimates of SMC/ MФ ratios are highly inaccurate. Even more importantly, we found that SMC can play either a beneficial or detrimental role in lesion pathogenesis depending on the nature of their phenotypic/functional transitions. For example, Klf4-dependent transitions, including formation of SMC-derived MФ-marker+ foam cells1 exacerbated lesion pathogenesis whereas Oct4-dependent transitions2 were atheroprotective including being critical for migration and investment of SMC into a protective fibrous cap. Indeed, remarkably, results of RNAseq and Oct4/Klf4 CHIPseq analyses of advanced brachiocephalic lesions from SMC Klf4 versus SMC Oct4 knockout mice showed virtually completely opposite genomic signatures. Taken together, results show that SMC play an absolutely critical, even dominant role, in late stage lesion pathogenesis in that conditional loss of a single gene in SMC can completely alter lesion pathogenesis [see our recent review3].

A major focus of our current studies is to identify factors, mechanisms, and potential therapeutic targets that can promote beneficial, and/or inhibit detrimental SMC phenotypic transitions within advanced lesions and thereby promote increased plaque stability. In addition, we are determining if mutations or gene polymorphisms that are linked to increased cardiovascular disease in humans may function, at least in part, by promoting detrimental changes in SMC phenotype and their associated functions. Finally, we have initiated additional studies investigating the potential role of SMC and pericyte phenotypic transitions in the pathogenesis of microvascular disease associated with Type II diabetes/metabolic disease, and in regulation of tumor cell growth and metastasis. The latter studies, which were published in Nature Medicine4 and done in collaboration with Dr. Kaplan’s lab at NIH, showed that highly metastatic tumor cells secrete factors that circulate in blood and induce Klf4-dependent reprogramming of SMC and pericytes within metastatic niches that make them permissive for tumor cell invasion and survival. Remarkably, we found that SMC-pericyte specific knockout of the stem cell pluripotency gene Klf4 dramatically reduced tumor metastasis by >70%.

Reference List:(1) Shankman LS, Gomez D, Cherepanova OA, Salmon M, Alencar GF, Haskins RM, Swiatlowska P, Newman AA, Greene ES, Straub AC, Isakson B, Randolph GJ, Owens GK. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat Med 2015 May 18;21(6):628-37.(2) Cherepanova OA, Gomez D, Shankman LS, Swiatlowska P, Williams J, Sarmento OF, Alencar GF, Hess DL, Bevard MH, Greene ES, Murgai M, Turner SD, Geng YJ, Bekiranov S, Connelly JJ, Tomilin A, Owens GK. Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective. Nat Med 2016 May 16;22(6):657-65.(3) Bennett MR, Sinha S, Owens GK. Vascular Smooth Muscle Cells in Atherosclerosis. Circ Res 2016 February 19;118(4):692-702.(4) Murgai M, Ju W, Eason M, Kline J, Beury DW, Kaczanowska S, Miettinen MM, Kruhlak M, Lei H, Shern JF, Cherepanova OA, Owens GK, Kaplan RN. KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis. Nat Med 2017 October;23(10):1176-90.

Selected Publications

  • Baylis R, Gomez D, Mallat Z, Pasterkamp G, Owens G. The CANTOS Trial: One Important Step for Clinical Cardiology but a Giant Leap for Vascular Biology. Arteriosclerosis, thrombosis, and vascular biology. 2017;37(11): e174-e177. PMID: 28970294
  • Baylis R, Gomez D, Owens G. Shifting the Focus of Preclinical, Murine Atherosclerosis Studies From Prevention to Late-Stage Intervention. Circulation research. 2017;120(5): 775-777. PMID: 28254801 | PMCID: PMC5338643
  • DiRenzo D, Owens G, Leeper N. "Attack of the Clones": Commonalities Between Cancer and Atherosclerosis. Circulation research. 2017;120(4): 624-626. PMID: 28209794
  • Durgin B, Cherepanova O, Gomez D, Karaoli T, Alencar G, Butcher J, Zhou Y, Bendeck M, Isakson B, Owens G, Connelly J. Smooth muscle cell-specific deletion of Col15a1 unexpectedly leads to impaired development of advanced atherosclerotic lesions. American journal of physiology. Heart and circulatory physiology. 2017;312(5): H943-H958. PMID: 28283548 | PMCID: PMC5451587
  • Murgai M, Ju W, Eason M, Kline J, Beury D, Kaczanowska S, Miettinen M, Kruhlak M, Lei H, Shern J, Cherepanova O, Owens G, Kaplan R. KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis. Nature medicine. 2017;23(10): 1176-1190. PMID: 28920957
  • Bennett M, Sinha S, Owens G. Vascular Smooth Muscle Cells in Atherosclerosis. Circulation research. 2016;118(4): 692-702. PMID: 26892967 | PMCID: PMC4762053
  • Cherepanova O, Gomez D, Shankman L, Swiatlowska P, Williams J, Sarmento O, Alencar G, Hess D, Bevard M, Greene E, Murgai M, Turner S, Geng Y, Bekiranov S, Connelly J, Tomilin A, Owens G. Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective. Nature medicine. 2016;22(6): 657-65. PMID: 27183216 | PMCID: PMC4899256
  • Gomez D, Owens G. Reconciling Smooth Muscle Cell Oligoclonality and Proliferative Capacity in Experimental Atherosclerosis. Circulation research. 2016;119(12): 1262-1264. PMID: 27932466 | PMCID: PMC5157924
  • Shankman L, Gomez D, Cherepanova O, Salmon M, Alencar G, Haskins R, Swiatlowska P, Newman A, Greene E, Straub A, Isakson B, Randolph G, Owens G. Corrigendum: KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nature medicine. 2016;22(2): 217. PMID: 26845408 | PMCID: PMC5102056
  • Cuttano R, Rudini N, Bravi L, Corada M, Giampietro C, Papa E, Morini M, Maddaluno L, Baeyens N, Adams R, Jain M, Owens G, Schwartz M, Lampugnani M, Dejana E. KLF4 is a key determinant in the development and progression of cerebral cavernous malformations. EMBO molecular medicine. 2015;8(1): 6-24. PMID: 26612856 | PMCID: PMC4718159
  • Gomez D, Swiatlowska P, Owens G. Epigenetic Control of Smooth Muscle Cell Identity and Lineage Memory. Arteriosclerosis, thrombosis, and vascular biology. 2015;35(12): 2508-16. PMID: 26449751 | PMCID: PMC4662608
  • Johnston W, Salmon M, Pope N, Meher A, Su G, Stone M, Lu G, Owens G, Upchurch G, Ailawadi G. Response to letter regarding article, "Inhibition of interleukin-1β decreases aneurysm formation and progression in a novel model of thoracic aortic aneurysm". Circulation. 2015;131(14): e400. PMID: 25847985
  • Nurnberg S, Cheng K, Raiesdana A, Kundu R, Miller C, Kim J, Arora K, Carcamo-Oribe I, Xiong Y, Tellakula N, Nanda V, Murthy N, Boisvert W, Hedin U, Perisic L, Aldi S, Maegdefessel L, Pjanic M, Owens G, Tallquist M, Quertermous T. Coronary Artery Disease Associated Transcription Factor TCF21 Regulates Smooth Muscle Precursor Cells That Contribute to the Fibrous Cap. PLoS genetics. 2015;11(5): e1005155. PMID: 26020946 | PMCID: PMC4447275
  • Nurnberg S, Cheng K, Raiesdana A, Kundu R, Miller C, Kim J, Arora K, Carcamo-Oribe I, Xiong Y, Tellakula N, Nanda V, Murthy N, Boisvert W, Hedin U, Perisic L, Aldi S, Maegdefessel L, Pjanic M, Owens G, Tallquist M, Quertermous T. Coronary Artery Disease Associated Transcription Factor TCF21 Regulates Smooth Muscle Precursor Cells that Contribute to the Fibrous Cap. Genomics data. 2015;5 36-37. PMID: 26090325 | PMCID: PMC4467834
  • Shankman L, Gomez D, Cherepanova O, Salmon M, Alencar G, Haskins R, Swiatlowska P, Newman A, Greene E, Straub A, Isakson B, Randolph G, Owens G. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nature medicine. 2015;21(6): 628-37. PMID: 25985364 | PMCID: PMC4552085
  • Tabas I, García-Cardeña G, Owens G. Recent insights into the cellular biology of atherosclerosis. The Journal of cell biology. 2015;209(1): 13-22. PMID: 25869663 | PMCID: PMC4395483
  • Wu J, Montaniel K, Saleh M, Xiao L, Chen W, Owens G, Humphrey J, Majesky M, Paik D, Hatzopoulos A, Madhur M, Harrison D. Origin of Matrix-Producing Cells That Contribute to Aortic Fibrosis in Hypertension. Hypertension (Dallas, Tex. : 1979). 2015;67(2): 461-8. PMID: 26693821 | PMCID: PMC4713264
  • Bhamidipati C, Whatling C, Mehta G, Meher A, Hajzus V, Su G, Salmon M, Upchurch G, Owens G, Ailawadi G. 5-Lipoxygenase pathway in experimental abdominal aortic aneurysms. Arteriosclerosis, thrombosis, and vascular biology. 2014;34(12): 2669-78. PMID: 25324573 | PMCID: PMC4239157
  • Ding D, Starke R, Dumont A, Owens G, Hasan D, Chalouhi N, Medel R, Lin C. Therapeutic implications of estrogen for cerebral vasospasm and delayed cerebral ischemia induced by aneurysmal subarachnoid hemorrhage. BioMed research international. 2014;2014 727428. PMID: 24724095 | PMCID: PMC3958795
  • Johnston W, Salmon M, Pope N, Meher A, Su G, Stone M, Lu G, Owens G, Upchurch G, Ailawadi G. Inhibition of interleukin-1β decreases aneurysm formation and progression in a novel model of thoracic aortic aneurysms. Circulation. 2014;130(11): S51-9. PMID: 25200056 | PMCID: PMC5097450
  • Starke R, Chalouhi N, Jabbour P, Tjoumakaris S, Gonzalez L, Rosenwasser R, Wada K, Shimada K, Hasan D, Greig N, Owens G, Dumont A. Critical role of TNF-α in cerebral aneurysm formation and progression to rupture. Journal of neuroinflammation. 2014;11 77. PMID: 24739142 | PMCID: PMC4022343
  • Gomez D, Shankman L, Nguyen A, Owens G. Detection of histone modifications at specific gene loci in single cells in histological sections. Nature methods. 2013;10(2): 171-7. PMID: 23314172 | PMCID: PMC3560316
  • Starke R, Ali M, Jabbour P, Tjoumakaris S, Gonzalez F, Hasan D, Rosenwasser R, Owens G, Koch W, Dumont A. Cigarette smoke modulates vascular smooth muscle phenotype: implications for carotid and cerebrovascular disease. PloS one. 2013;8(8): e71954. PMID: 23967268 | PMCID: PMC3743809
  • Alexander M, Murgai M, Moehle C, Owens G. Interleukin-1β modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-κB-dependent mechanisms. Physiological genomics. 2012;44(7): 417-29. PMID: 22318995 | PMCID: PMC3339851
  • Gomez D, Owens G. Smooth muscle cell phenotypic switching in atherosclerosis. Cardiovascular research. 2012;95(2): 156-64. PMID: 22406749 | PMCID: PMC3388816
  • Nguyen A, Gomez D, Bell R, Campbell J, Clowes A, Gabbiani G, Giachelli C, Parmacek M, Raines E, Rusch N, Speer M, Sturek M, Thyberg J, Towler D, Weiser-Evans M, Yan C, Miano J, Owens G. Smooth Muscle Cell Plasticity: Fact or Fiction? Circulation research. 2012. PMID: 23093573
  • Salmon M, Gomez D, Greene E, Shankman L, Owens G. Cooperative binding of KLF4, pELK-1, and HDAC2 to a G/C repressor element in the SM22α promoter mediates transcriptional silencing during SMC phenotypic switching in vivo. Circulation research. 2012;111(6): 685-96. PMID: 22811558 | PMCID: NIHMS401822
  • Alexander M, Moehle C, Johnson J, Yang Z, Lee J, Jackson C, Owens G. Genetic inactivation of IL-1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice. The Journal of clinical investigation. 2011;122(1): 70-9. PMID: 22201681 | PMCID: PMC3248279
  • Alexander M, Owens G. Epigenetic control of smooth muscle cell differentiation and phenotypic switching in vascular development and disease. Annual review of physiology. 2011;74 13-40. PMID: 22017177
  • Gan Q, Thiébaud P, Thézé N, Jin L, Xu G, Grant P, Owens G. WD repeat-containing protein 5, a ubiquitously expressed histone methyltransferase adaptor protein, regulates smooth muscle cell-selective gene activation through interaction with pituitary homeobox 2. The Journal of biological chemistry. 2011;286(24): 21853-64. PMID: 21531708 | PMCID: PMC3122240
  • Hoofnagle M, Neppl R, Berzin E, Teg Pipes G, Olson E, Wamhoff B, Somlyo A, Owens G. Myocardin is differentially required for the development of smooth muscle cells and cardiomyocytes. American journal of physiology. Heart and circulatory physiology. 2011;300(5): H1707-21. PMID: 21357509 | PMCID: PMC3094091
  • Jin L, Gan Q, Zieba B, Goicoechea S, Owens G, Otey C, Somlyo A. The actin associated protein palladin is important for the early smooth muscle cell differentiation. PloS one. 2010;5(9): e12823. PMID: 20877641 | PMCID: PMC2943901
  • Yoshida T, Gan Q, Franke A, Ho R, Zhang J, Chen Y, Hayashi M, Majesky M, Somlyo A, Owens G. Smooth and cardiac muscle-selective knock-out of Kruppel-like factor 4 causes postnatal death and growth retardation. The Journal of biological chemistry. 2010;285(27): 21175-84. PMID: 20439457 | PMCID: PMC2898332
  • Cherepanova O, Pidkovka N, Sarmento O, Yoshida T, Gan Q, Adiguzel E, Bendeck M, Berliner J, Leitinger N, Owens G. Oxidized phospholipids induce type VIII collagen expression and vascular smooth muscle cell migration. Circulation research. 2009;104(5): 609-18. PMID: 19168440 | PMCID: PMC2758767
  • Deaton R, Gan Q, Owens G. Sp1-dependent activation of KLF4 is required for PDGF-BB-induced phenotypic modulation of smooth muscle. American journal of physiology. Heart and circulatory physiology. 2009;296(4): H1027-37. PMID: 19168719 | PMCID: PMC2670704
  • Nickerson M, Song J, Meisner J, Bajikar S, Burke C, Shuptrine C, Owens G, Skalak T, Price R. Bone marrow-derived cell-specific chemokine (C-C motif) receptor-2 expression is required for arteriolar remodeling. Arteriosclerosis, thrombosis, and vascular biology. 2009;29(11): 1794-801. PMID: 19734197 | PMCID: PMC2766019
  • Jin L, Yoshida T, Ho R, Owens G, Somlyo A. The actin-associated protein Palladin is required for development of normal contractile properties of smooth muscle cells derived from embryoid bodies. The Journal of biological chemistry. 2008;284(4): 2121-30. PMID: 19015263 | PMCID: PMC2629081
  • Shang Y, Yoshida T, Amendt B, Martin J, Owens G. Pitx2 is functionally important in the early stages of vascular smooth muscle cell differentiation. The Journal of cell biology. 2008;181(3): 461-73. PMID: 18458156 | PMCID: PMC2364692
  • Thomas J, Deaton R, Hastings N, Shang Y, Moehle C, Eriksson U, Topouzis S, Wamhoff B, Blackman B, Owens G. PDGF-DD, a novel mediator of smooth muscle cell phenotypic modulation, is upregulated in endothelial cells exposed to atherosclerosis-prone flow patterns. American journal of physiology. Heart and circulatory physiology. 2008;296(2): H442-52. PMID: 19028801 | PMCID: PMC2643880
  • Wamhoff B, Lynch K, Macdonald T, Owens G. Sphingosine-1-phosphate receptor subtypes differentially regulate smooth muscle cell phenotype. Arteriosclerosis, thrombosis, and vascular biology. 2008;28(8): 1454-61. PMID: 18535287 | PMCID: PMC2605659
  • Yoshida T, Gan Q, Owens G. Kruppel-like factor 4, Elk-1, and histone deacetylases cooperatively suppress smooth muscle cell differentiation markers in response to oxidized phospholipids. American journal of physiology. Cell physiology. 2008;295(5): C1175-82. PMID: 18768922 | PMCID: PMC2584997
  • Yoshida T, Kaestner K, Owens G. Conditional deletion of Krüppel-like factor 4 delays downregulation of smooth muscle cell differentiation markers but accelerates neointimal formation following vascular injury. Circulation research. 2008;102(12): 1548-57. PMID: 18483411 | PMCID: PMC2633447
  • Gan Q, Yoshida T, Li J, Owens G. Smooth muscle cells and myofibroblasts use distinct transcriptional mechanisms for smooth muscle alpha-actin expression. Circulation research. 2007;101(9): 883-92. PMID: 17823374
  • McDonald O, Owens G. Programming smooth muscle plasticity with chromatin dynamics. Circulation research. 2007;100(10): 1428-41. PMID: 17525382
  • Pidkovka N, Cherepanova O, Yoshida T, Alexander M, Deaton R, Thomas J, Leitinger N, Owens G. Oxidized phospholipids induce phenotypic switching of vascular smooth muscle cells in vivo and in vitro. Circulation research. 2007;101(8): 792-801. PMID: 17704209
  • Gan Q, Yoshida T, McDonald O, Owens G. Concise review: epigenetic mechanisms contribute to pluripotency and cell lineage determination of embryonic stem cells. Stem cells (Dayton, Ohio). 2006;25(1): 2-9. PMID: 17023513
  • Gorenne I, Jin L, Yoshida T, Sanders J, Sarembock I, Owens G, Somlyo A, Somlyo A. LPP expression during in vitro smooth muscle differentiation and stent-induced vascular injury. Circulation research. 2006;98(3): 378-85. PMID: 16397143
  • Kawai-Kowase K, Owens G. Multiple repressor pathways contribute to phenotypic switching of vascular smooth muscle cells. American journal of physiology. Cell physiology. 2006;292(1): C59-69. PMID: 16956962
  • Khromov A, Wang H, Choudhury N, McDuffie M, Herring B, Nakamoto R, Owens G, Somlyo A, Somlyo A. Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca2+ and decreased cGMP-induced relaxation. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(7): 2440-5. PMID: 16461919 | PMCID: PMC1413704
  • McDonald O, Wamhoff B, Hoofnagle M, Owens G. Control of SRF binding to CArG box chromatin regulates smooth muscle gene expression in vivo. The Journal of clinical investigation. 2006;116(1): 36-48. PMID: 16395403 | PMCID: PMC1323266
  • Sinha S, Wamhoff B, Hoofnagle M, Thomas J, Neppl R, Deering T, Helmke B, Bowles D, Somlyo A, Owens G. Assessment of contractility of purified smooth muscle cells derived from embryonic stem cells. Stem cells (Dayton, Ohio). 2006;24(7): 1678-88. PMID: 16601077
  • Yoshida T, Gan Q, Shang Y, Owens G. Platelet-derived growth factor-BB represses smooth muscle cell marker genes via changes in binding of MKL factors and histone deacetylases to their promoters. American journal of physiology. Cell physiology. 2006;292(2): C886-95. PMID: 16987998