Department of Anesthesiology/Critical Care Medicine
The Johns Hopkins University School of Medicine
Sheikh Zayed Tower 6208
1800 Orleans Street
Baltimore, MD 21287
Healthy blood vessels are compliant and flexible, but with age, the vasculature can become stiff. Dr. Daniel Nyhan, with Dr. Dan Berkowitz, is interested in studying these vascular changes that accompany aging, determining the underlying causes, and finding ways to reverse the process. They use a technique based on wave-form analysis (which is somewhat similar to ultrasound) to determine the rate at which a pulse wave is transmitted and reflected, an index known as pulse-wave velocity. 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. Patients with high pulse pressure (the difference between the systolic and diastolic pressures) are at greater risk for stroke, renal failure, and death, than those with normal pulse pressure.
Drs. Nyhan and Berkowitz, with their colleague Dr. Artin Shoukas, are trying to determine the factors that mediate vascular stiffness. One avenue that they are researching is 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.
- Member Departmental Residency Recruitment/Interview Committee
- Chief, Division of Cardiac Anesthesia Services
- Member, Departmental Service Executive Committee
- Executive Vice Chairman, ACCM
- Steppan J, Ryoo S, Schuleri KH, Gregg C, Hasan RK, White AR, Bugaj LJ, Khan M, Santhanam L, Nyhan D, Shoukas AA, Hare JM, Berkowitz DE. Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism. Proc Natl Acad Sci USA. 103:4759–64, 2006.
- Benjo A, Thompson RE, Fine D, Hogue CW, Alejo D, Kaw A, Gerstenblith G, Shah A, Berkowitz DE, Nyhan D. Pulse pressure is an age-independent predictor of stroke development after cardiac surgery. Hypertension 50:630–5, 2007.
- 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 arginase1 contributes to age-related endothelial dysfunction.Circ Res 101:692–702, 2007.
- 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. Am J Physiol Heart Circ Physiol 293:H3317–24, 2007.
- Ryoo S, Gupta G, Benjo A, Lim HK, Camara A, Sikka G, Sohi J, Santhanam L, Soucy K, Tuday E, Baraban E, Ilies 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 102(8):923–32, 2008.
Laboratory Members/Key Associates
- Dan Berkowitz, MD
- Gary Gerstenblith, MD (Department of Cardiology)
- Sungwoo Ryoo, MD
- Lakshmi Santhanam, PhD
- Artin Shoukas, PhD