Research

My laboratory is interested in various aspects of vascular biology, in particular vascular disorders associated with menopause, diabetes and hypertension. Calmodulin is the most important transducer of intracellular Ca²⁺ signals by virtue of its requirement for the functions of numerous cellular proteins and its insufficient expression for all its targets. Modulating aspects of calmodulin-dependent signaling thus represents therapeutic potential for many cardiovascular disorders. We use a combination of molecular, cellular and biochemical approaches coupled with multi-wavelength intracellular imaging techniques to investigate the mechanisms and therapeutic options for alterations in calmodulin-dependent signaling associated with menopause, diabetes and hypertension. Currently we are focusing on two main areas: 

1. Regulation of GPER-mediated signaling in the vasculature by calmodulin: Despite the clear linkage between postmenopause and cardiovascular disease, hormone replacement therapy has not proven to be cardioprotective. The novel G protein-coupled estrogen receptor 1 (GPER, or GPR30) has been implicated in a vast array of cardiovascular functions, cancer, bone development, brain functions, and reproductive functions.  Studies in this project aim at identifying GPER as a novel calmodulin-binding protein and test the overall hypothesis that GPER activation triggers in the vasculature feed-forward mechanisms that involve calmodulin both at the receptor level and downstream effectors, linking signaling pathways mediated by different estrogen receptors. The role of GPER in intracellular Ca²⁺ signaling and cell-cell interaction via modulation of calmodulin-dependent activities are also being examined. We are developing novel biosensors that allow studies of specific interactions between GPER and other binding partners. We expect that these studies will provide timely information that help form the basis for targeting estrogen receptor subtypes for preventive and therapeutic purposes.
2. Intercellular interactions in the control of vascular functions: Vascular endothelial cells and smooth muscle cells are two principal cell types of vascular tissue. Interactions between these two cell types are essential in the coordinated regulation of vascular functions. We are investigating paracrine and autocrine mechanisms of intercellular interactions in the vasculature via calmodulin-dependent activities through which endothelial and smooth muscle cell functions are coordinated. Novel models of primary vascular cells for intercellular studies and intracellular imaging, coupled with other molecular and biochemical approaches are employed. These studies are expected to reveal novel mechanisms governing intercellular interactions in physiological processes such as angiogenesis and vasculogenesis, and disease states associated with endothelial regeneration following vascular injuries.

These studies are currently supported by the National Institutes of Health (HL112184) and the Iowa Osteopathic and Educational Research Funds (IOER-R&G).

Publications

1. Persechini A, Tran QK, Black DJ, Gogol EP. Calmodulin facilitates electron transfer in endothelial nitric oxide synthase by positioning the reductase domains near the oxygenase domains. FEBS Letters 2013; 587:297-301. Epub ahead of print Dec 22, 2012

Tran QK, Leonard J, Black DJ, Persechini A. Effects of combined phosphorylation at Ser-617 and Ser-1179 in endothelial nitric oxide synthase on EC50(Ca2+) values for calmodulin binding and enzyme activation. J. Biol Chem; 284(18): 11892-11899., 2009

Tran QK, Leonard J, Black DJ, Persechini A. Phosphorylation within an Autoinhibitory Domain in Endothelial Nitric Oxide Synthase Reduces the Ca2+ Concentrations Required for Calmodulin To Bind and Activate the Enzyme. Biochemistry;47(28):7557-66., 2008

Tran Q-K, Watanabe H. Calcium signaling in the endothelium. (Book Chapter) In: The Vascular Endothelium (Handbook of Experimental Pharmacology, Vol. 176: 145-187; 2006) Edited by Moncada S. and Higgs A. ISBN: 3- 540-32966-8., 2006

Tran Q-K, Black DJ, Persechini A. Dominant affectors in the calmodulin network shape the time courses of target responses in the cell. Cell Calcium;37(6):541-553., 2005

Black DJ, Tran Q-K, Persechini A. Monitoring the total available calmodulin concentration in intact cells over the physiological range in free Ca2+. Cell Calcium; 35(5):415-25 , 2004

Takeuchi K, Watanabe H, Tran Q-K, Ozeki M, Sumi D, Hayashi T, Iguchi A, Ignarro LJ, Ohashi K, Hayashi H. Nitric oxide: inhibitory effects on endothelial cell calcium signaling, prostaglandin I2 production and nitric oxide synthase expression. Cardiovasc Res;62:194-201., 2004

Tran Q-K, Watanabe H. Myosin Light Chain Kinase in Endothelial Cell Calcium Signaling and Endothelial Functions. Book Chapter In: Atherosclerosis, Hypertension and Diabetes (Book series: Progress in Experimental Cardiology. Vol. 8, pp 163-174; 2003). Edited by Pierce G.N., Nagano M, Zahradka P, and Dhalla NS. Kluwer Academic/Plenum Publishers. ISBN 1-4020-7311-9., 2003

Tran Q-K, Black DJ, Persechini A. Intracellular coupling via limiting calmodulin. J. Biol. Chem.;278(27):24247- 50., 2003

Takeuchi K, Watanabe H, Tran Q-K, Ozeki M, Uehara A, Katoh H, Satoh H, Terada H, Hayashi H. Effects of cytochrome P450 inhibitors on agonist-induced Ca2+ responses and production of NO and PGI2 in vascular endothelial cells. Mol Cell Biochem.;248(1-2):129-34., 2003

Watanabe H, Ohashi K, Takeuchi K, Yamashita K, Yokoyama T, Tran Q-K, Satoh H, Terada H, Ohashi H, Hayashi H. Sildenafil for primary and secondary pulmonary hypertension. Clin Pharmacol Ther.;71(5):398-402., 2002

Tran Q-K, Watanabe H, Le H-Y, Takeuchi K, Hattori Y, Tomioka H, Ohashi K, Hayashi H. Insulin inhibits coronary endothelial cell Ca2+ entry and coronary artery relaxation. J Cardiovas Pharmacol; 38 (6):885-892., 2001

Tran Q-K, Watanabe H, Le H-Y, Ling P, Seto M, Takeuchi K, Ohashi K. Myosin light chain kinase regulates capacitative Ca2+ entry in human monocytes/macrophages. Arterioscler Thromb Vasc Biol;21; 509-515., 2001

Watanabe H, Tran Q-K, Takeuchi K, Fukao M, Liu MY, Kanno M, Hayashi T, Iguchi A, Seto M, Ohashi K. Myosin light-chain kinase regulates endothelial Ca2+ entry and endothelium-derived vasodilation. FASEB J.; 15 (2):282-284., 2001

Tomioka H, Hattori Y, Fukao M, Watanabe H, Akaishi Y, Sato A, Tran Q-K, Sakuma I, Kitabatake A, Kanno M. Role of endothelial Ni2+-sensitive Ca2+ entry pathway in regulation of EDHF in porcine coronary artery. Am J Physiol Heart Circ Physiol; 280:H730-H737., 2001

Tran Q-K, Ohashi K, Watanabe H. Calcium signalling in endothelial cells. (Review) Cardiovasc Res.;48(1):13- 22., 2000

Tran Q-K, Watanabe H, Le H-Y, Yang J, Takeuchi K, Kadomatsu K, Muramatsu T, Ohashi K. Midkine inhibits bradykinin-induced endothelial Ca2+ signaling and nitric oxide production. Biochem Biophys Res Commun.; 276;830-836., 2000

Fukao M, Hattori H, Sato A, Liu MY, Watanabe H, Tran Q-K, Kanno M. Relationship between NaF- and thapsigargin-induced endothelium-dependent hyperpolarization in rat mesenteric artery. Brit J Pharmacol.;126:1567-1574., 1999

Watanabe H, Takahashi R, Tran Q-K, Takeuchi K, Kosuge K, Satoh H, Uehara A, Terada H, Hayashi H, Ohno R, Ohashi K. Increased cytosolic Ca2+ concentration in endothelial cells by calmodulin antagonists. Biochem Biophys Res Commun.;265:697-702., 1999

Tran Q-K, Watanabe H, Zhang XX, Takahashi R, Ohno R. Involvement of myosin light chain kinase in chloride- sensitive Ca2+ influx in porcine aortic endothelial cells. Cardiovasc Res.;44:623-631., 1999

Awards and honors

2012-2014 - Academic Enhancement Research Award, National Institutes of Health

2012 - Distinguished Scholar Award, Des Moines University

2001 - International Exchange Travel Award (Shizuoka, Japan)

1997-2001 - Fellow of the Ministry of Education, Culture and Science of Japan

1996-1997 - Fellow of the Asian Youth Fellowship Program, Japanese Government