Canonical TRP channels (TRPC) form store- and receptor-operated Ca2+-permeable channels in the plasma membrane of vascular smooth muscle cells. TRPCs have been implicated in regulating vascular tone and smooth muscle cell proliferation. This proposal will define the molecular roles of TRPC channels during coronary artery remodeling associated with metabolic syndrome (MetS). MetS is characterized by central obesity, elevated plasma cholesterol and fasting glucose, hypertension, insulin resistance, and atherosclerosis. The prevalence of MetS among adults in the USA is 24%. In this research program, we will utilize the MetS Ossabaw pig model that exhibits all of the characteristics of MetS, including the overactive renin-angiotensin- aldosterone system (RAAS). We demonstrated that the expression levels of TRPC1 and TRPC6 channels are markedly elevated in MetS Ossabaw pig coronary arteries exhibiting atherosclerosis and hypercontractility. Consistently, freshly isolated MetS coronary artery smooth muscle cells had elevated store-/receptor-operated Ca2+ influx and large store-/receptor-operated TRPC-like currents. Since angiotensin II and aldosterone are positive regulators of TRPC expression, we hypothesize that, in MetS, the overactive RAAS upregulates TRPC1 and TRPC6 expression, which drives increased coronary smooth muscle cell proliferation and coronary artery hypercontractility. The following Specific Aims will be pursued: 1) To determine how the molecular expression of TRPCs is altered during the MetS-associated remodeling of coronary artery smooth muscle cells;2) To define the contribution of TRPCs to endogenous store- and receptor-activated Ca2+ influx/currents in control and MetS coronary artery smooth muscle cells;3) To determine whether the functional expression of endogenous TRPC channels is directly regulated by RAAS components, angiotensin II and Aldo, in coronary artery smooth muscle cells;4) To determine whether the in vivo, coronary artery targeted down- regulation of TRPCs slows atheroma progression and decreases coronary artery hypercontractility in MetS pigs. During this research program, we will use molecular biological, biochemical, electrophysiological, and fluorescence imaging approaches as well as intravascular ultrasound, isometric tension and coronary artery ring lumen area measurements. Additionally, a coronary artery targeted delivery approach will be employed to deploy shRNAs and cDNA constructs into the coronary artery wall in vivo. Importantly, we will determine the distinct roles of TRPC1 and TRPC6 during MetS-associated NATIVE atherosclerosis progression.
The results of this study will determine the molecular mechanisms involved in regulating TRPC channel expression in atherosclerotic MetS coronary arteries and define the channel's role in MetS-associated coronary dysfunctions.
|Chen, Xingjuan; Li, Wennan; Hiett, S Christopher et al. (2016) Novel Roles for Kv7 Channels in Shaping Histamine-Induced Contractions and Bradykinin-Dependent Relaxations in Pig Coronary Arteries. PLoS One 11:e0148569|
|Zhang, Wenlin; Ogando, Diego G; Bonanno, Joseph A et al. (2015) Human SLC4A11 Is a Novel NH3/H+ Co-transporter. J Biol Chem 290:16894-905|
|Chen, Xingjuan; Egly, Christian; Riley, Ashley M et al. (2014) PKC-dependent Phosphorylation of the H1 Histamine Receptor Modulates TRPC6 Activity. Cells 3:247-57|
|Chen, Xingjuan; Sun, Weiyang; Gianaris, Nicholas G et al. (2014) Furanocoumarins are a novel class of modulators for the transient receptor potential vanilloid type 1 (TRPV1) channel. J Biol Chem 289:9600-10|
|Luo, Na; Conwell, Michael D; Chen, Xingjuan et al. (2014) Primary cilia signaling mediates intraocular pressure sensation. Proc Natl Acad Sci U S A 111:12871-6|
|Hiett, S Christopher; Owen, Meredith K; Li, Wennan et al. (2014) Mechanisms underlying capsaicin effects in canine coronary artery: implications for coronary spasm. Cardiovasc Res 103:607-18|
|Berwick, Zachary C; Dick, Gregory M; O'Leary, Heather A et al. (2013) Contribution of electromechanical coupling between Kv and Ca v1.2 channels to coronary dysfunction in obesity. Basic Res Cardiol 108:370|