Dr. Nyhan is interested in studying the vascular changes that accompany aging, determining the underlying causes and finding ways to reverse the process. With Dr. Dan Berkowitz, he uses a technique based on wave-form analysis to determine the rate at which a pulse wave is transmitted and reflected. The stiffer the blood vessel, the more quickly the pulse wave travels. In a clinical study, they found that not only do noncompliant blood vessels reduce cardiovascular function; the condition results in poorer outcome after cardiac surgery.
Drs. Nyhan and Berkowitz, with their colleague Dr. Artin Shoukas, are trying to determine the factors that mediate vascular stiffness. They are researching the effect of an enzyme known as arginase-II, found in the endothelial cells that line blood vessels. The amino acid arginine is required for the production of nitric oxide (NO) by nitric oxide synthase (NOS). NO is a critical molecule for the relaxation of vascular smooth muscle, and hence, vasorelaxation. However, arginase competes with NOS for the utilization of arginine; an elevation in arginase could lead to decreased production of NO and stiffer blood vessels.
In a recent study, their laboratory found that arginase inhibition improved NO production and decreased vascular stiffness in a preclinical model of atherosclerosis. Additional benefits were decreased production of reactive oxygen species and a decrease in total cholesterol plaque burden. Currently, researchers are trying to develop an inhibitor of arginase that can be used clinically.
Dr. Nyhan finds it highly gratifying to have the opportunity to work clinically and in the laboratory, and to see the relevance of each to the other. His hope is that in the future, this work in vascular biology will lead to new ways to improve vascular compliance and thereby improve cardiovascular function and perioperative risk.
Publications Since 2006
1. White AR, Ryoo SW, Li D, Champion HC, Steppan J, Wang D, Nyhan D, Shoukas AA, Hare JM, Berkowitz DE. Knockdown of arginase 1 restores NO signaling in the vasculature of old rats. Hypertension 2006; 47:245-251.
2. Gao WD, Da T, Nyhan D. Increased cross-bridge cycling rate in stunned myocardium. Am J Physiol Heart Circ Physiol 2006;290:H866-H893.
3. Steppan J, Ryoo S, Schuleri KH, Gregg C, Hasan RK, White AR, Bugaj LJ, Khan M, Santhanam L, Nyhan D, Shoukas A, Hare J, Berkowitz DE. Arginase modulates myocardial contractility by a nitric oxide synthase-1 dependent mechanism. PNAS USA. 2006;103:4759-4764.
4. Ryoo S, Lemmon C, Soucy KG, Gupta G, White AR, Nyhan D, Shoukas A, Romer LH, Berkowitz DE. Oxidized low-density lipoprotein-dependent endothelial arginase Hi activation contributes to impaired nitric oxide signaling. Circ Res. 2006;99: 951-960.
5. Soucy KG, Ryoo S, Benjo A, Lim HK, Gupta G, Sohi JS, Elser J, Aon MA, Nyhan D, Shoukas AA, Berkowitz DE. Impaired shear stress-induced nitric oxide production through decreased NOS phosphorylation contributes to age-related vascular stiffeness. JAppI Physiol 2006;101:1751-1759.
6. Lim HK, Lim HK, Ryoo S, Benjo A, Shuleri K, Miriel V, Baraban E, Camara A, Soucy K, Nyhan D, Shoukas A, Berkowitz DE. Mitochondrial arginase II constrains endothelial NOS-3 activity. AJP-Heart, Lung, Physiol. 2007;93:H3317-H3324.
7. Berkowitz DE, Nyhan D. Critical role of the alpha-1 B adrenoreceptors in sympathetically-mediated pressor and contractile responses to hypotension. Circulation. In Review.
8. Benjo A, Thompson RE, Fine D, Hogue CW, Alejo D, Kaw A, Gerstenblith G, Shah A, Berkowitz DE, Nyhan D. Pulse pressure predicts stroke development and acute renal failure after cardiac surgery. Hypertension. 2007;50:630-635.
9a. Tuday EC, Meek JV, Nyhan D, Shoukas AA, Berkowitz DE. Microgravity-induced changes in aortic
stiffness and their role in orthostatic intolerance, J Appl Physiol, 2007;102:853-858.
9b. Associated Editorial: to be published in J Appl Physiol 2007;103:1-2.
10. Santhanam L, Lim HK, Lim HK, Miriel V, Brown T, Patel M, Balanson S, Ryoo S, Anderson M, Irani K, Khanday F, Di Costanzo L, Nyhan D, Hare JM, Christianson DW, Rivers R, Shoukas A, Berkowitz DE. Inducible NO synthase dependent S-nitrosylation and activation of arginasel contributes to age-related endothelial dysfunction. Circ Res. 2007;101:692-702.
11. Lim HK, Lim HK, Ryoo S, Benjo A, Shuleri K, Miriel V, Baraban E, Camara A, Soucy K, Nyhan D, Shoukas A, Berkowitz DE. Mitochondrial arginase II constrains endothelial NOS-3 activity. AJP - Heart, Circ Physiol. 2007;293:H3317-H3324.
12. Ryoo S, Gupta G, Benjo A, Lim HK, Camara A, Sikka G, Lim HK, Sohi J, Santhanam L, Soucy K, tuday E, Baraban E, Hies M, Gerstenblith G, Nyhan D, Shoukas A, Christianson DW, Alp NJ, Champion HC, Huso D, Berkowitz DE. Endothelial arginase II: a novel target for the treatment of atherosclerosis, Circ Res. Circ Res. 2008;102:923-943.
13. Tuday EC, Nyhan D, Shoukas AA, Berkowitz DE. Microgravity induced changes in aortic stiffness and its role in orthostatic intolerance, J Appl Physiol, 2007;102:853-858.
14. Nyhan D, Berkowitz DE. Perioperative blood pressure management: does central vascular stiffness matter? Anesth Analg. 2008;107:1103-1106.
Chapters and Reviews since 2006
1. Grogan K, Nyhan D, Berkowitz DE. Pharmacology of anesthetic drugs. IN: Cardiac Anesthesia; 5th Edition. JA Kaplan, D Reich, S Konstade, C Lake, eds. Elsevier/Saunders, New York, 2006. Chap 9, pp 165-212.
2. Nyhan D, BlanckTJJ. Cardiac physiology. IN: Mechanisms of Anesthetic Action, 2nd Edition. IN: Basic and Applied Science for Anesthesia. HC Hemmings, Jr., PM Hopkins, eds. CV Mosby, London; Chapter 39.
3. Steppan J, Berkowitz DE, Martinez E, Nyhan D. Diastolic heart function and the elderly. IN: Aging and Anesthesia. F Sieber, ed. McGraw-Hill, Philadelphia, Chapter 16, 2006.
4. Simmonds P, Nyhan D, Berkowitz DE. Cardiovascular pharmacological agents. IN: The Johns Hopkins Manual of Cardiac Surgical Care, 2nd Edition. Eds. JV Conte, WA Baumgartner, SG Owens, T Dorman. Elsevier, Philadelphia, PA. Chapter 2, 2008.
5. Dorman T, Nyhan D. Postoperative hemodynamic management. IN: The Johns Hopkins Manual of Cardiac Surgical Care, 2nd Edition. Eds. JV Conte, WA Baumgartner, SG Owens, T Dorman. Elsevier, Philadelphia, PA. Chapter 9, 2008.
6. Grogan K, Nyhan D, Berkowitz D. Pharmacology of anesthetic drugs. IN: Cardiac Anesthesia, &h Edition. JA Kaplan, D Reich, S Konstade, C Lake, eds. Elsevier/Saunders, New York. Chapter 7, 2008.