Maintenance of Normal Blood Pressure is Dependent on IP3R1-mediated Regulation of ENOS

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2016 Jul 13

PMID 27402766

Citations 42

Authors

Qi Yuan

Jingyi Yang

Gaetano Santulli

Steven R Reiken

Anetta Wronska

Mindy M Kim

Brent W Osborne

Alain Lacampagne

Yuxin Yin

Andrew R Marks

Affiliations

Soon will be listed here.

Abstract

Endothelial cells (ECs) are critical mediators of blood pressure (BP) regulation, primarily via the generation and release of vasorelaxants, including nitric oxide (NO). NO is produced in ECs by endothelial NO synthase (eNOS), which is activated by both calcium (Ca(2+))-dependent and independent pathways. Here, we report that intracellular Ca(2+) release from the endoplasmic reticulum (ER) via inositol 1,4,5-trisphosphate receptor (IP3R) is required for Ca(2+)-dependent eNOS activation. EC-specific type 1 1,4,5-trisphosphate receptor knockout (IP3R1(-/-)) mice are hypertensive and display blunted vasodilation in response to acetylcholine (ACh). Moreover, eNOS activity is reduced in both isolated IP3R1-deficient murine ECs and human ECs following IP3R1 knockdown. IP3R1 is upstream of calcineurin, a Ca(2+)/calmodulin-activated serine/threonine protein phosphatase. We show here that the calcineurin/nuclear factor of activated T cells (NFAT) pathway is less active and eNOS levels are decreased in IP3R1-deficient ECs. Furthermore, the calcineurin inhibitor cyclosporin A, whose use has been associated with the development of hypertension, reduces eNOS activity and vasodilation following ACh stimulation. Our results demonstrate that IP3R1 plays a crucial role in the EC-mediated vasorelaxation and the maintenance of normal BP.

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References

Matoba T, Shimokawa H, Nakashima M, Hirakawa Y, Mukai Y, Hirano K . Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. J Clin Invest. 2000; 106(12):1521-30. PMC: 387255. DOI: 10.1172/JCI10506. View

van Gelder T, van Schaik R, Hesselink D . Pharmacogenetics and immunosuppressive drugs in solid organ transplantation. Nat Rev Nephrol. 2014; 10(12):725-31. DOI: 10.1038/nrneph.2014.172. View

Crowley S, Gurley S, Coffman T . AT(1) receptors and control of blood pressure: the kidney and more. Trends Cardiovasc Med. 2007; 17(1):30-4. DOI: 10.1016/j.tcm.2006.11.002. View

Kochukov M, Balasubramanian A, Abramowitz J, Birnbaumer L, Marrelli S . Activation of endothelial transient receptor potential C3 channel is required for small conductance calcium-activated potassium channel activation and sustained endothelial hyperpolarization and vasodilation of cerebral artery. J Am Heart Assoc. 2014; 3(4). PMC: 4310376. DOI: 10.1161/JAHA.114.000913. View

Shesely E, Maeda N, Kim H, Desai K, Krege J, Laubach V . Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1996; 93(23):13176-81. PMC: 24066. DOI: 10.1073/pnas.93.23.13176. View

Rinne A, Banach K, Blatter L . Regulation of nuclear factor of activated T cells (NFAT) in vascular endothelial cells. J Mol Cell Cardiol. 2009; 47(3):400-10. PMC: 2779755. DOI: 10.1016/j.yjmcc.2009.06.010. View

Palmer R, Ashton D, Moncada S . Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988; 333(6174):664-6. DOI: 10.1038/333664a0. View

Chataigneau T, Feletou M, Huang P, Fishman M, DUHAULT J, Vanhoutte P . Acetylcholine-induced relaxation in blood vessels from endothelial nitric oxide synthase knockout mice. Br J Pharmacol. 1999; 126(1):219-26. PMC: 1565804. DOI: 10.1038/sj.bjp.0702300. View

Santulli G, Ciccarelli M, Palumbo G, Campanile A, Galasso G, Ziaco B . In vivo properties of the proangiogenic peptide QK. J Transl Med. 2009; 7:41. PMC: 2702279. DOI: 10.1186/1479-5876-7-41. View

10.

Zbroch E, Malyszko J, Mysliwiec M, Przybylowski P, Durlik M . Hypertension in solid organ transplant recipients. Ann Transplant. 2012; 17(1):100-7. DOI: 10.12659/aot.882641. View

11.

Zetterqvist A, Blanco F, Ohman J, Kotova O, Berglund L, de Frutos Garcia S . Nuclear factor of activated T cells is activated in the endothelium of retinal microvessels in diabetic mice. J Diabetes Res. 2015; 2015:428473. PMC: 4396720. DOI: 10.1155/2015/428473. View

12.

Lanni F, Santulli G, Izzo R, Rubattu S, Zanda B, Volpe M . The Pl(A1/A2) polymorphism of glycoprotein IIIa and cerebrovascular events in hypertension: increased risk of ischemic stroke in high-risk patients. J Hypertens. 2007; 25(3):551-6. DOI: 10.1097/HJH.0b013e328013cd67. View

13.

Santulli G, Pagano G, Sardu C, Xie W, Reiken S, DAscia S . Calcium release channel RyR2 regulates insulin release and glucose homeostasis. J Clin Invest. 2015; 125(5):1968-78. PMC: 4463204. DOI: 10.1172/JCI79273. View

14.

Iaccarino G, Ciccarelli M, Sorriento D, Cipolletta E, Cerullo V, Iovino G . AKT participates in endothelial dysfunction in hypertension. Circulation. 2004; 109(21):2587-93. DOI: 10.1161/01.CIR.0000129768.35536.FA. View

15.

Xie W, Santulli G, Guo X, Gao M, Chen B, Marks A . Imaging atrial arrhythmic intracellular calcium in intact heart. J Mol Cell Cardiol. 2013; 64:120-3. PMC: 4387875. DOI: 10.1016/j.yjmcc.2013.09.003. View

16.

Ritter O, Schuh K, Brede M, Rothlein N, Burkard N, Hein L . AT2 receptor activation regulates myocardial eNOS expression via the calcineurin-NF-AT pathway. FASEB J. 2002; 17(2):283-5. DOI: 10.1096/fj.02-0321fje. View

17.

Lackland D, Weber M . Global burden of cardiovascular disease and stroke: hypertension at the core. Can J Cardiol. 2015; 31(5):569-71. DOI: 10.1016/j.cjca.2015.01.009. View

18.

Nguyen H, Chiasson V, Chatterjee P, Kopriva S, Young K, Mitchell B . Interleukin-17 causes Rho-kinase-mediated endothelial dysfunction and hypertension. Cardiovasc Res. 2012; 97(4):696-704. PMC: 3583258. DOI: 10.1093/cvr/cvs422. View

19.

Blacher J, Levy B, Mourad J, Safar M, Bakris G . From epidemiological transition to modern cardiovascular epidemiology: hypertension in the 21st century. Lancet. 2016; 388(10043):530-2. DOI: 10.1016/S0140-6736(16)00002-7. View

20.

Koch-Weser J . Vasodilator drugs in the treatment of hypertension. Arch Intern Med. 1974; 133(6):1017-27. View