Griendling cardiovascular lab
The Griendling basic science cardiology laboratory focuses on the role of reactive oxygen species in smooth muscle proliferation, migration and differentiation, and the role of oxidative stress in the pathogenesis of vascular disease.
Dr. Griendling and her colleagues were among the first to recognize that the vasoactive peptide, angiotensin II, activates a non-phagocytic NADPH oxidase in vascular smooth muscle, and that this enzyme contributes to the pathophysiology of vascular disease. Subsequent work by Griendling and her colleagues showed that Nox1 and Nox4 are major sources of reactive oxygen species in the vasculature. Importantly, Nox1 and Nox4 are differentially localized, have distinct agonist specificity, produce different ratios of ROS, and regulate specific cellular functions. Thus, Nox1 is found in caveolae, is activated by growth-promoting agonists such as Angiotensin II and PDGF, and produces mainly superoxide. In contrast, Nox4 is localized to the nucleus, to stress fibers in differentiated cells and focal adhesions in growing cells, is down regulated by Angiotensin II and PDGF but induced by TGF-beta , and produces mainly H2O2.
Based on the results of past basic science work there are four major areas of ongoing research in the lab:
• The signaling pathways by which Nox4 mediates vascular smooth muscle cell differentiation are being studied. In addition the role of Nox4 in focal adhesion formation and stress fiber assembly is under investigation.
• The redox-sensitive signal transduction pathways by which reactive oxygen species derived from Nox proteins mediate vascular smooth muscle cell migration. The cytoskeletal protein cofilin has emerged as a major target of Nox1, and current work is focused on the regulation of the actin-associated cytoskeleton by reactive oxygen species.
• The p22phox-interacting protein, Poldip2, the first known regulator of Nox4 is being studied. This protein has profound effects on cytoskeletal dynamics, cell growth and extracellular matrix production. The phenotype of newly created knockout mice is currently under investigation.
• The use of transgenic and knockout mice to investigate the role of the novel NADPH oxidases in vascular disease. Mice overexpressing Nox1 or p22phox and mice deficient in Nox1, Nox4 or Poldip2 are being studied with respect to vascular dysfunction in collateral formation and vascular injury.
Selected 2014 Publications
Poldip2 controls vascular smooth muscle cell migration by regulating focal adhesion turnover and force polarization.
Datla SR, McGrail DJ, Vukelic S, Huff LP, Lyle AN, Pounkova L, Lee M, Seidel-Rogol B, Khalil MK, Hilenski LL, Terada LS, Dawson MR, Lassegue B, Griendling KK. Am J Physiol Heart Circ Physiol. 2014 Oct 1;307(7):H945-57.
Polymerase Delta-Interacting Protein 2 Promotes Postischemic Neovascularization of the Mouse Hindlimb. Amanso AM, Lassegue B, Joseph G, Land¡zuri N, Long JS, Weiss D, Taylor WR, Griendling KK. Arterioscler Thromb Vasc Biol. 2014 May 22. PMID: 24855063
Poldip2 knockout results in perinatal lethality, reduced cellular growth and increased autophagy of mouse embryonic fibroblasts.
Brown DI, Lassegue B, Lee M, Zafari R, Long JS, Saavedra HI, Griendling KK.
PLoS One. 2014 May 5;9(5):e96657. PMID: 24797518
NADPH oxidases: progress and opportunities.
San Martin A, Griendling KK.
Antioxid Redox Signal. 2014 Jun 10;20(17):2692-4. PMID: 24730700
Angiotensin II, from vasoconstrictor to growth factor: a paradigm shift.
Vukelic S, Griendling KK.
Circ Res. 2014 Feb 28;114(5):754-7. PMID: 24577962
Selected 2013 Publications
Transforming Growth Factor Inhibits Platelet Derived Growth Factor-Induced Vascular Smooth Muscle Cell Proliferation via Akt-Independent, Smad-Mediated Cyclin D1 Downregulation.
Martan-Garrido A, Williams HC, Lee M, Seidel-Rogol B, Ci X, Dong JT, Lassegue B, Martin AS, Griendling KK.
PLoS One. 2013 Nov 13;8(11):e79657.
Polymerase delta interacting protein 2 sustains vascular structure and function.
Sutliff RL, Hilenski LL, Amanso AM, Parastatidis I, Dikalova AE, Hansen L, Datla SR, Long JS, El-Ali AM, Joseph G, Gleason RL Jr, Taylor WR, Hart CM, Griendling KK, Lassegue B. Arterioscler Thromb Vasc Biol. 2013 Sep;33(9):2154-61.
|PubMed| PDF |
The bone morphogenic protein inhibitor, noggin, reduces glycemia and vascular inflammation in db/db mice.
Koga M, Engberding N, Dikalova AE, Chang KH, Seidel-Rogol B, Long JS, Lassegue B, Jo H, Griendling KK.
Am J Physiol Heart Circ Physiol. 2013 Sep 1;305(5):H747-55.
Differential roles of NADPH oxidases in vascular physiology and pathophysiology.
Amanso AM, Griendling KK.
Front Biosci (Schol Ed). 2012 Jan 1;4:1044-64.
Vascular smooth muscle insulin resistance, but not hypertrophic signaling, is independent of angiotensin II-induced IRS-1 phosphorylation by JNK.
Hitomi H, Mehta PK, Taniyama Y, Lassegue B, Seidel-Rogol B, San Martin A, Griendling KK.
Am J Physiol Cell Physiol. 2011 Dec;301(6):C1415-22.
Platelet-derived growth factor (PDGF) regulates Slingshot phosphatase activity via Nox1-dependent auto-dephosphorylation of serine 834 in vascular smooth muscle cells.
Maheswaranathan M, Gole HK, Fernandez I, Lassegue B, Griendling KK, San Martan A.
J Biol Chem. 2011 Oct 14;286(41):35430-7.
ADPH oxidase 4 mediates TGF-induced smooth muscle actin via p38MAPK and serum response factor.
Martin-Garrido A, Brown DI, Lyle AN, Dikalova A, Seidel-Rogol B, Lassegue B, San Martan A, Griendling KK.
Free Radic Biol Med. 2011 Jan 15;50(2):354-62.
Mechanisms of vascular smooth muscle NADPH oxidase 1 (Nox1) contribution to injury-induced neointimal formation.
Lee MY, San Martin A, Mehta PK, Dikalova AE, Garrido AM, Datla SR, Lyons E, Krause KH, Banfi B, Lambeth JD, Lassegue B, Griendling KK.
Arterioscler Thromb Vasc Biol. 2009 Apr;29(4):480-7.
Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells.
Lyle AN, Deshpande NN, Taniyama Y, Seidel-Rogol B, Pounkova L, Du P, Papaharalambus C, Lassegue B, Griendling KK.
Circ Res. 2009 Jul 31;105(3):249-59.
Selected Publications from Previous Years:
Distinct roles of Nox1 and Nox4 in basal and angiotensin II-stimulated superoxide and hydrogen peroxide production.
Dikalov SI, Dikalova AE, Bikineyeva AT, Schmidt HH, Harrison DG, Griendling KK.
Free Radic Biol Med. 2008 Nov 1;45(9):1340-51.
Nox5 mediates PDGF-induced proliferation in human aortic smooth muscle cells.
Jay DB, Papaharalambus CA, Seidel-Rogol B, Dikalova AE, Lassegue B, Griendling KK.
Free Radic Biol Med. 2008 Aug 1;45(3):329-35.
Clempus RE, Sorescu D, Dikalova AE, Pounkova L, Jo P, Sorescu GP, Schmidt HH, Lassegue B, Griendling KK.
Nox4 is required for maintenance of the differentiated vascular smooth muscle cell phenotype.
Arterioscler Thromb Vasc Biol. 2007, 27:42-8.
Dikalova A, Clempus R, Lassegue B, Cheng G, McCoy J, Dikalov S, San Martin A, Lyle A, Weber DS, Weiss D, Taylor WR, Schmidt HH, Owens GK, Lambeth JD, Griendling KK.
Nox1 overexpression potentiates angiotensin II-induced hypertension and vascular smooth muscle hypertrophy in transgenic mice.
Circulation, 2005, 112:2668-76.
Weber DS, Rocic P, Mellis AM, Laude K, Lyle AN, Harrison DG, Griendling KK.
Angiotensin II-induced hypertrophy is potentiated in mice overexpressing p22phox in vascular smooth muscle
Am J Physiol Heart Circ Physiol., 2005, 288:H37-42.
Hanna IR, Hilenski LL, Dikalova A, Taniyama Y, Dikalov S, Lyle A, Quinn MT, Lassegue B, Griendling KK.
Functional association of nox1 with p22phox in vascular smooth muscle cells
Free Radic Biol Med., 2004, 37(10): 1542-9.
Hilenski LL, Clempus RE, Quinn MT, Lambeth JD, Griendling KK.
Distinct Subcellular Localizations of Nox1 and Nox4 in Vascular Smooth Muscle Cells
Arterioscler Thromb Vasc Biol., 2004, 24:677-683.
Deshpande NN, Sorescu D, Seshiah P, Ushio-Fukai M, Akers M, Yin Q, Griendling KK.
Mechanism of hydrogen peroxide-induced cell cycle arrest in vascular smooth muscle
Antioxid. Redox Signal., 2002, 4(5):845-854.
Seshiah PN, Weber DS, Rocic P, Valppu L, Taniyama Y, Griendling KK.
Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators
Circ. Res., 2002, 91(5):406-413.
Sorescu D, Weiss D, Lassegue B, Clempus RE, Szcs K, Sorescu GP, Valppu L, Quinn MT, Lambeth JD, Vega JD, Taylor WR, Griendling KK.
Superoxide production and expression of nox family proteins in human atherosclerosis
Circulation, 2002, 105(12):1429-35.
Szcs K, Lassegue B, Sorescu D, Hilenski LL, Valppu L, Couse TL, Wilcox JN, Quinn MT, Lambeth JD, Griendling KK.
Upregulation of Nox-based NAD(P)H oxidases in restenosis after carotid injury
Arterioscler. Thromb. Vasc. Biol., 2002, 22(1): 21-27.
Lassegue B, Sorescu D, Scs K, Yin Q, Akers M, Zhang Y, Grant SL, Lambeth JD, Griendling KK
Novel gp91(phox) homologues in vascular smooth muscle cells : nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways
Circ. Res., 2001, 88(9):888-894.
Suh Y, Arnold RS, Lassegue B, Shi J, Xu X, Sorescu D, Chung AB, Griendling KK, Lambeth JD
Cell transformation by the superoxide-generating oxidase mox1
Nature, 1999, 401: 79-82.
Zafari AM, Ushio-Fukai M, Akers M, Yin Q, Shah A, Harrison DG, Taylor WR, Griendling KK
Role of NADH/NADPH oxidase-derived H2O2 in angiotensin II-induced vascular hypertrophy
Hypertension, 1998, 32(3): 488-495.
Ushio-Fukai M, Zafari AM, Fukui T, Ishizaka N, Griendling KK
p22phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells
J. Biol. Chem., 1996, 271: 23317-23321.
Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW
Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells
Circ. Res., 1994, 74: 1141-1148.
The Griendling lab is led by Kathy Griendling,
|Dr. Griendling is a professor of medicine in the Division of Cardiology at Emory University and is also the vice chair for research and faculty development in the Emory University Department of Medicine.|
Division of Cardiology
101 Woodruff Circle
Woodruff Memorial Research Building 308
Atlanta, GA 30322