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Dan E. Berkowitz M.B.BCh
Professor, Dept. of ACCM
410.614.1517

dberkow1@jhmi.edu
  Integrated Cardiovascular Research
Understanding Mechanisms that Underlie Vascular Disorders
 
 

Translational Vascular Medicine: Bridging Research and Clinical Vascular Therapy 

Hydrogen Sulfide and the Regulation of Vascular Function in Health and Disease

Kir6.1 subunit of the KATP Channel: Sulfhydration of cysteine-34 activates the channel causing hyperpolarization.

Recently, hydrogen sulfide (H2S), which has been identified as a gaseous mediator (much like NO), mediates physiologic processes including vasodilation by vascular smooth muscle (VSMC) hyperpolarization. We have recently demonstrated that H2S is indeed an Endothelial Derived Hyperpolarization Factor (EDHF) which mediates its effects by, a novel redox-sensitive post translational modification called Sulfhydration (SHY). SHY of VSMC ATP-sensitive K+ (KATP) channels leads to hyperpolarization and vascular relaxation. Furthermore H2S is endogenously generated during cysteine metabolism by the enzyme cystathionine-γ-lyase (CSE).   Our laboratory continues to explore the role of CSE and its product hydrogen sulfide in the pathobiology of septic shock and hypertension.  

Read recent publication: "Hydrogen Sulfide as Endothelium -Derived Hyperpolarizing Factor Sulfhydrates Potassium Channels" 



Development of Arginase Inhibitors and Novel Therapies for Cardiovascular Diseases


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Endothelial dysfunction is a critical component and precursor of vascular diseases including atherosclerosis, hypertension, and aging. Nitric Oxide is an important vasoprotective molecule produced by the enzyme nitric oxide synthase (NOS), and the bioavailability of this molecule is decreased in these diseases.  One of the major conundrums regarding the pathobiology of these diseases is that the abundance of NOS is increased rather than decreased.  This led us to propose that another mechanism might be contributing to the decreased NO bioavailability, and therefore lack of vascular protection. In ongoing work supported by the NIA and NHLBI we have identified an enzyme, Arginase , that reciprocally regulates NOS.  It does so by competing for a common substrate, L-Arginine.  We have shown that this enzyme is upregulated/activity increased in the blood vessels of aging and atherosclerotic animals.  Furthermore, inhibition of the enzyme leads to an increase in the production of protective nitric oxide and improvement in endothelial function.

Given the prevalence of cardiovascular disease, there remains continued interest in novel classes of vascular  therapies.  Our  work, presented at the Hopkins Alliance meeting created interest by a local venture capital/incubator company, Acidophil.  In collaboration with Dr. David Christianson, a University of Pennsylvania Biochemist who had crystallized the enzyme arginase and synthesized novel inhibitors of the enzyme, the company Arginetix was created.  With ongoing support from Acidophil, and the recruitment of a founding CEO, Gary Lessing, the company received venture funding to develop arginase inhibitors and novel therapies for cardiovascular diseases.  In 2011, Arginetix  merged with Immune Control to create Corridor Pharmaceuticals Inc. and received a further infusion of venture capital.



Mechanisms and Mitigation of Radiation Induced Endothelial Dysfunction

 
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Space radiation has the potential to accelerate the pathogenesis of early-stage cardiovascular disease in astronauts on long-duration missions. The cardiovascular alterations team of the NSBRI set out to determine the role of oxidative stress and nitroso-redox imbalance in radiation-induced endothelial dysfunction. Specifically, the contribution of xanthine oxidase, a ROS-producing enzyme which plays a role in the pathobiology of endothelial dysfunction was examined. The effects of endothelial cell-targeted anti-senescence therapy, such as xanthine oxidase (XO) inhibitors, arginase inhibitors and statins were tested as protectants against endothelial cell dysfunction and injury. Our team has confirmed that ionizing radiation is detrimental to vascular health, endothelial function, regeneration, and angiogenic potential. Oxidative stress is a critical contributing factor with XO being the primary source of ROS in response to radiation. This implies that inhibition of XO may be an effective defense against radiation injury by reducing ROS, enhancing vasoprotective nitric oxide production, and rescuing endothelial cell proliferative ability and angiogenic potential. Indeed, these effects are observed with single doses of iron ion radiation as low as 50cGy.


Nitric Oxide Regulation of Tissue Transglutaminase (TG2): Role in Age-Related Vascular Stiffness and Systolic Hypertension

 
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Vascular stiffness has been clearly established as a risk factor for cardiovascular disease, and is an independent predictor of cardiovascular morbidity and mortality. Aging is associated with increased vascular stiffness and isolated systolic hypertension, which results from alterations in the properties of all elements of the vascular wall including endothelium, vascular smooth muscle, and matrix. Although both dynamic (alterations in endothelial function and effects on vascular smooth contractility), as well as structural (eg. fracturing of elastin) have been described in aging, molecular mechanisms underlying age-related vascular stiffness remain poorly understood. Thus targeted therapy remains elusive. Tissue transglutaminase (TG2, tTG), expressed in vascular endothelial, smooth muscle cells, and fibroblasts, enzymatically forms cross-links between extracellular matrix proteins, and may contribute to this pathobiology. Ca2+-dependent activation of TG2 is dependent on its externalization to the cell surface. Recently, it has been demonstrated that S-nitrosylation, a redox-sensitive post-translational modification of cysteine residues, leads to TG2 enzyme inhibition. In preliminary data, we demonstrate that TG2 is S-nitrosylated in cellular models and that this leads to decreased cell-surface localization and decreased cross-linking activity. Using  TG2-/- mice, we show that TG2 is the primary TGase mediating stiffness of conduit arteries, and that it is regulated by endothelium-derived NO. We further demonstrate in aging rat and human aorta, that TG2 activity is increased, and its S-nitrosylation is decreased despite unchanged TG2 abundance. Finally, inhibition of TG in old rats reduces vascular stiffness. It is now well established that NO bioavailability is diminished and reactive oxygen species (ROS) are increased in aging. Given this change in the nitroso-redox balance, we hypothesize that aging is associated with decreased TG2 S-nitrosylation and therefore, increased externalization and increased matrix cross-linking activity, and TG2-dependent downstream signaling. Together, these result in increased vessel stiffness, and ultimately impaired vascular function, a hallmark of aging (Schematic 1). In this grant, we propose to determine the role of NO in the regulation of TG2 location, activity and downstream signaling, and determine whether this enzyme is a critical target in age-related vascular stiffness. 
  

 

Research Application Funding

The Berkowitz Lab research in vascular physiology and pathobiology is quite diverse, as reflected by the sources of funding that support it.  Much of the lab's funding is provided by well-known agencies, foundations, associations, and industry groups.
 

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The National Heart Lung and Blood Institute (NHLBI,) as well as the National Institute on Aging (NIA) of the National Institutes of Health, have supported the laboratory's work through the funding of R01 grant proposals. 
S-nitrosylation of TG2

Both NASA and National Space Biomedical Research Institute continue to fund projects in the lab exploring the potential effects of deep space radiation on vascular function. 

The American Heart Association is currently funding one of our Post-Doctoral fellows who is exploring the mechanism of action of the endothelial derived hyperpolarizing factor and novel gaseous messenger hydrogen sulfide (H2S). 

Flight Attendant Medical Research Institute, an Institute that is charged with  examining the health effects of second hand smoke, was established by flight attendants following litigation of the Tobacco Industry.  We are currently completing a project that examines the mechanism underlying second hand smoke induced endothelial dysfunction, and acceleration of atherosclerosis. 
 

 

Discovering how basic cellular processes are altered in disease states Developing therapies for vascular diseasesHelping lead space research team


Dr Dan Berkowitz is a Professor of Anesthesiology and Critical Care Medicine, and Biomedical Engineering at Johns Hopkins. He directs an integrated cardiovascular biology lab which has ongoing funding from the NIH, NASA and the National Space Biomedical Research Institute (NSBRI).  The primary focus of his  laboratory work  is geared toward understanding the role of nitroso-redox  regulation and dyregulation in vascular biology and pathobiology, particularly as it relates to aging, atherosclerosis, and radiation induced vascular endothelial function.

Mentoring undergraduate and graduate students as well as postdoctoral fellows

Dr. Berkowitz has mentored many biomedical engineering student undergraduates, graduate students and post-doctoral candidates. He loves to teach his students how to think about molecular mechanisms of disease processes, and how to apply basic science to solve them. Dr. Berkowitz asserts that the work that he and his students are doing will have important implications for understanding and treating  vascular disease. many of his students have gone on to graduate education  and have earned PhD and MD degrees from prestigious institutions around the country.  For example, Guarav Gupta far left of the  picture has just graduated from Stanford University Medical School and will be beginning his residency in Neurosurgery this summer.  Chris Gregg (center) is completing his PhD in Biomedical Sciences at the University of California, San Diego.
 


Discovering new therapies for vascular endothelial dysfunction

His laboratory has characterized the role of the enzyme arginase in the pathobiology of vascular endothelial dysfunction associated with aging and atherosclerosis. Arginase competes for the common amino acid substrate L-arginine with the enzyme nitric oxide synthase (NOS). Upregulation of arginase in these disease leads to a decrease in the production of the vasodilator and vasoprotective gas nitric oxide (NO) by the endothelial cells that line the blood vessels, as well as an increase in reactive species production by NOS (NOS uncoupling). Arginase inhibition can restore NOS coupling and improve endothelial function and vascular compliance in old rats and atherosclerotic mice thus representing a novel therapy for these diseases.


Understanding mechanisms of vascular dysfunction caused by radiation

With funding from NASA and NSBRI, Dr Berkowitz continues to characterize the effects of radiation on vascular endothelial function. Epidemiologic studies of Radiologists and well as people exposed to high levels of radiation (atomic bomb and nuclear accident survivors), suggest that cardiovascular risk is significantly increased. The mechanism underlying this phenomenon and countermeasures have not been well characterized. It is well known that radiation can cause cells in the body to produce damaging molecules known as reactive oxygen species (ROS).  Dr. Berkowitz and his graduate student Kevin Soucy are conducting experiments at the NASA Space Research Laboratory at Brookhaven National Laboratory. There, they have access to a particle accelerator, which creates radiation similar to what astronauts could encounter. In animal studies, the team have examined the effect of radiation on endothelial cell function and vascular health. Thus far they have demonstrated that the high-energy radiation activates an enzyme called xanthine oxidase (XO) that produces ROS. Furthermore, XO inhibition can interrupt this cycle of oxidant stress to the cells and thereby limit the damage. This ability to target the XO enzyme could have additional applications, such as for patients who need radiotherapy. 
 


Our laboratory is  using real time measures of coronary blood flow and coronary reserve in mice to determine the effect of radiation on coronary endothelial function in-vivo. This is accomplished with high resolution echo imaging and doppler measurements.


Discovering novel mechanisms of vascular stiffness and its regulation of nitric oxide

Vascular stiffness is a potent predictor of cardiovascular morbidity. Although increased systolic blood pressure and increased vascular stiffness are observed in older patients, and chronological age is the dominant and independent risk factor for cardiovascular disease, it is clear that age-related cardiovascular changes are not inevitable and are potentially modifiable by understanding and interrogating the underlying mechanisms.  Tissue transglutaminase (TG2, tTG), expressed in vascular endothelial, smooth muscle cells, and fibroblasts, enzymatically forms cross-links between extracellular matrix proteins, and may contribute to this pathobiology, Given the paucity of molecular targets specifically contributing to vascular stiffness and isolated systolic hypertension, we plan to determine the role of the critical nitroso-redox environment in regulating the activity of TG2 in aging. Furthermore we continue to study whether indeed TG2, a crosslinking enzyme, for which highly potent and specific small molecules might be developed, is an important target in isolated systolic hypertension.


Aorta of young rat with little TG mediated crosslinks (green stain).

Aorta of old rat showing heavy TG mediated crosslinks.
 

The monotonically increasing PWV with mean arterial pressure indicates that the aorta becomes stiffer with pressure. However, different PWV values for the same pressure may indicate that the artery is inherently stiffer, and the increase in PWV could be due to an increase in the Young’s modulus of the wall (E) or changes in wall thickness (h) or radius (R), according to the Moens-Korteweg relation: PWV = √(Eh/2ρR); where ρ is blood density. Thus increased stiffness in the aorta is may be different for changing arterial properties. Using a dual pressure catheter we are able to measure the instantaneous  pressure-PWV relationship allowing us to gain insights into the stiffness properties of the aorta in vivo.

Clip of dual arterial pressure measurement in rat. EKG 
serves as the fixed reference point for measurement of 
PWV 
MP-PWV relationship in old and young rats. At all pressures, PWV is higher  in old rats confirming an intrinsic alteration in the vascular stiffness properties 

 



 


News and Events

October 2011

Our manuscript entitled "Hydrogen Sulfide as Endothelium -Derived Hyperpolarizing Factor Sulfhydrates Potassium Channels" was recently published on in in Circulation Research.  Congratulations to Asif, Gautam and the team for a huge effort. 

September 2011

I was present  at the External advisory meeting of the NSBRI, which for the first time was held in the new shared Biopark Research Building shared by Baylor, Texas Children's, NSBRI and Rice University.  The building is located close to the  the Rice campus 

Ben Levine at entrance to NSBRI Consortium UniversitiesCardiovascular Alterations Team 

August 2011

Our manuscript entitled "HZE (56)Fe-Ion Irradiation Induces Endothelial Dysfunction in Rat Aorta: Role of Xanthine Oxidase." was recently published in the journal Radiation Research.  Congratulations to Kevin Soucy and the team for this huge effort and accomplishment 

June 2011

6/12/2011: Our work in radiation-related cardiovascular injury was highlighted in the Hopkins Medicine Magazine which is sent to all faculty and Alumi.  The article is titled "Cosmic Mission"




May 2011

Accolades for collaborative publication: Our collaborators, Dr Larry Kenney and  Lacy Holwatz received the distinction of "Editors choice" for a recently published paper  in the Journal of Physiology! 

5/27/2011: Congratulations to Kevin Soucy on this great milestone -- Graduating with a PhD in Biomedical Engineering.  Fantastic accomplishment!!! A great honor for our lab this week.


Publications

Gebska MA, Stevenson BK, Hemnes AR, Bivalacqua TJ, Haile A, Hesketh GG, Murray CI, Zaiman AL, Halushka MK, Krongkaew N, Strong TD, Cooke CA, El-Haddad H, Tuder RM, Berkowitz DE, Champion HC.  Phosphodiesterase-5A (PDE5A) is localized to the endothelial caveolae and modulates NOS3 activity.  Cardiovasc Res. 2011 Mar 18. [Epub ahead of print]
 
 
Yang R, Sikka G, Larson J, Watts VL, Niu X, Ellis C, Miller K, Camara A, Reinke C, Savransky V, Polotsky VY, O'Donnell CP, Berkowitz DE, Barouch LA. Restoring Leptin Signaling Reduces Hyperlipidemia and Improves Vascular Stiffness Induced by Chronic Intermittent Hypoxia.  Am J Physiol Heart Circ Physiol. 2011 Jan 28. [Epub ahead of print] PubMed PMID: 21278136.
 
 
Ryoo S, Bhunia A, Chang F, Shoukas A, Berkowitz DE, Romer LH. OxLDL-dependent activation of arginase II is dependent on the LOX-1 receptor and downstream RhoA signaling. 2011 Feb;214(2):279-87. Epub 2010 Nov 4. PubMed PMID: 21130456; PubMed Central PMCID: PMC3031764.
 
 
Gregg CJ, Steppan J, Gonzalez DR, Champion HC, Phan AC, Nyhan D, Shoukas AA, Hare JM, Barouch LA, Berkowitz DE. β2-adrenergic receptor-coupled phosphoinositide 3-kinase constrains cAMP-dependent increases in cardiac inotropy through phosphodiesterase 4 activation. Anesth Analg. 2010 Oct;111(4):870-7. Epub 2010 Aug 12. PubMed PMID: 20705779.
 
 
Goel A, Su B, Flavahan S, Lowenstein CJ, Berkowitz DE, Flavahan NA. Increased endothelial exocytosis and generation of endothelin-1 contributes to constriction of aged arteries.Circ Res. 2010 Jul 23;107(2):242-51. Epub 2010 Jun 3. PubMed PMID: 20522806; PubMed Central PMCID: PMC2909353.
 
 
White AR, Ryoo S, Bugaj L, Attarzadeh DO, Thiyagarajan S, Chen K, Attwater S, Abbot B, Li D, Champion HC, Shoukas AA, Nyhan D, Hare JM, Berkowitz DE, Tuday EC. Early changes in vasoreactivity after simulated microgravity are due to an upregulation of the endothelium-dependent nitric oxide/cGMP pathway.  Eur J Appl Physiol. 2010 Sep;110(2):395-404. Epub 2010 May 29. PubMed PMID: 20512503.
 
 
Santhanam L, Tuday EC, Webb AK, Dowzicky P, Kim JH, Oh YJ, Sikka G, Kuo M, Halushka MK, Macgregor AM, Dunn J, Gutbrod S, Yin D, Shoukas A, Nyhan D, Flavahan NA, Belkin AM, Berkowitz DE. Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness.  Circ Res. 2010 Jul 9;107(1):117-25. Epub 2010 May 20. PubMed PMID: 20489165.
 
 
Soucy KG, Attarzadeh DO, Ramachandran R, Soucy PA, Romer LH, Shoukas AA, Berkowitz DE. Single exposure to radiation produces early anti-angiogenic effects in mouse aorta. Radiat Environ Biophys. 2010 Aug;49(3):397-404. Epub 2010 Apr 18. PubMed PMID: 20401726.
 
 
Soucy KG, Lim HK, Attarzadeh DO, Santhanam L, Kim JH, Bhunia AK, Sevinc B, Ryoo S, Vazquez ME, Nyhan D, Shoukas AA, Berkowitz DE. Dietary inhibition of xanthine oxidase attenuates radiation-induced endothelial dysfunction in rat aorta. J Appl Physiol. 2010 May;108(5):1250-8. Epub 2010 Feb 18. PubMed PMID: 20167676.
 
 
Sikka G, Yang R, Reid S, Benjo A, Koitabashi N, Camara A, Baraban E, O'Donnell CP, Berkowitz DE, Barouch LA. Leptin is essential in maintaining normal vascular compliance independent of body weight.  Int J Obes (Lond). 2010 Jan;34(1):203-6. Epub 2009 Oct 6. PubMed PMID: 19806156.
 
 
Kim JH, Bugaj LJ, Oh YJ, Bivalacqua TJ, Ryoo S, Soucy KG, Santhanam L, Webb A, Camara A, Sikka G, Nyhan D, Shoukas AA, Ilies M, Christianson DW, Champion HC, Berkowitz DE. Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats.  J Appl Physiol. 2009Oct;107(4):1249-57. Epub 2009 Aug 6. PubMed PMID: 19661445; PubMed Central PMCID: PMC2763842.
 
 
Tuday EC, Nyhan D, Shoukas AA, Berkowitz DE. Simulated microgravity-induced aortic remodeling.  J Appl Physiol. 2009 Jun;106(6):2002-8. Epub 2009 Mar 19. PubMed PMID: 19299573; PubMed Central PMCID: PMC2692776.
 
 
Bivalacqua TJ, Sussan TE, Gebska MA, Strong TD, Berkowitz DE, Biswal S, Burnett AL, Champion HC. Sildenafil inhibits superoxide formation and prevents endothelial dysfunction in a mouse model of secondhand smoke induced erectile dysfunction.J Urol. 2009 Feb;181(2):899-906. Epub 2008 Dec 17. PubMed PMID: 19095260.
 
 
Hughes JM, Wirth O, Krajnak K, Miller R, Flavahan S, Berkowitz DE, Welcome D, Flavahan NA. Increased oxidant activity mediates vascular dysfunction in vibration injury.  J Pharmacol Exp Ther. 2009 Jan;328(1):223-30. Epub 2008 Oct 27. PubMed PMID: 18955588.
 
 
Nyhan D, Berkowitz DE. Perioperative blood pressure management: does central vascular stiffness matter?  Anesth Analg. 2008 Oct;107(4):1103-6. PubMed PMID: 18806011.
 
 
Santhanam L, Christianson DW, Nyhan D, Berkowitz DE. Arginase and vascular aging.J Appl Physiol. 2008 Nov;105(5):1632-42. Epub 2008 Aug 21. Review. PubMed  PMID: 18719233; PubMed Central PMCID: PMC2584835.
 
 
Santhanam L, Gucek M, Brown TR, Mansharamani M, Ryoo S, Lemmon CA, Romer L, Shoukas AA, Berkowitz DE, Cole RN. Selective fluorescent labeling of S-nitrosothiols (S-FLOS): a novel method for studying S-nitrosation.. Nitric Oxide. 2008 Nov;19(3):295-302. Epub 2008 Jul 30. PubMed PMID: 18706513.
 
 
Ryoo S, Gupta G, Benjo A, Lim HK, Camara A, Sikka G, Lim HK, 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. 2008 Apr 25;102(8):923-32. Epub 2008 Feb 28. PubMed PMID: 18309100.
 
 
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. 2007 Dec;293(6):H3317-24. Epub 2007 Sep 7. PubMed PMID: 17827260.
 
 
Benjo A, Thompson RE, Fine D, Hogue CW, Alejo D, Kaw A, Gerstenblith G, ShahA, Berkowitz DE, Nyhan D. Pulse pressure is an age-independent predictor of stroke development after cardiac surgery.  Hypertension. 2007 Oct;50(4):630-5. Epub 2007 Sep 4. PubMed PMID: 17785628.
 
 
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 contribute to age-related endothelial dysfunction.. Circ Res. 2007 Sep 28;101(7):692-702. Epub 2007 Aug 17. PubMed PMID: 17704205.
 
 
Tuday EC, Berkowitz DE. Microgravity and cardiac atrophy: no sex discrimination.J Appl Physiol. 2007 Jul;103(1):1-2. Epub 2007 Mar 15. PubMed PMID: 17363626.
 
 
Soucy KG, Lim HK, Benjo A, Santhanam L, Ryoo S, Shoukas AA, Vazquez ME, Berkowitz DE. Single exposure gamma-irradiation amplifies xanthine oxidase activity and induces endothelial dysfunction in rat aorta.Radiat EnvironBiophys. 2007 Jun;46(2):179-86. Epub 2007 Jan 26. PubMed PMID: 17256177.
 
 
Berkowitz DE. Myocyte nitroso-redox imbalance in sepsis: NO simple answer.. Circ Res. 2007 Jan 5;100(1):1-4. Review. PubMed PMID: 17204656.
 
 
Soucy KG, Ryoo S, Benjo A, Lim HK, Gupta G, Sohi JS, Elser J, Aon MA, Nyhan  D, Shoukas AA, Berkowitz DEImpaired shear stress-induced nitric oxide production through decreased NOS phosphorylation contributes to age-related vascular stiffness.. J Appl Physiol. 2006 Dec;101(6):1751-9. PubMed PMID: 17106067.
 
 
Tuday EC, Meck JV, Nyhan D, Shoukas AA, Berkowitz DE. Microgravity-induced changes in aortic stiffness and their role in orthostatic intolerance.. J Appl Physiol. 2007 Mar;102(3):853-8. Epub 2006 Nov 2. PubMed PMID: 17082368.
 
 
Ryoo S, Lemmon CA, Soucy KG, Gupta G, White AR, Nyhan D, Shoukas A, Romer LH, Berkowitz DE. Oxidized low-density lipoprotein-dependent endothelial arginase II activation contributes to impaired nitric oxide signaling.Circ Res. 2006 Oct 27;99(9):951-60. Epub 2006 Sep 28. PubMed PMID: 17008605.
 
 
Ryoo S, Santhanam L, Nyhan D, Berkowitz DEResponse to Does Arginase Activity In Vitro Represent That In Vivo?Hypertension. 2006 Aug 28. [Epub ahead of print] PubMed PMID: 16940211.
 
 
Raju SV, Zheng M, Schuleri KH, Phan AC, Bedja D, Saraiva RM, Yiginer O, Vandegaer K, Gabrielson KL, O'donnell CP, Berkowitz DE, Barouch LA, Hare JM.  Activation of the cardiac ciliary neurotrophic factor receptor reverses left ventricular hypertrophy in leptin-deficient and leptin-resistant obesity.. Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4222-7. Epub 2006 Mar 6. PubMed PMID: 16537512; PubMed Central PMCID: PMC1449674.
 
 
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 U S A. 2006 Mar 21;103(12):4759-64. Epub 2006 Mar 13. PubMed PMID:  16537391; PubMed Central PMCID: PMC1450243.
 
 
White AR, Ryoo S, Li D, Champion HC, Steppan J, Wang D, Nyhan D, Shoukas AA, Hare JM, Berkowitz DE. Knockdown of arginase I restores NO signaling in the vasculature of old rats.. 2006 Feb;47(2):245-51. Epub 2005 Dec 27. PubMed PMID: 16380531.
 
 
Barouch LA, Gao D, Chen L, Miller KL, Xu W, Phan AC, Kittleson MM, Minhas KM, Berkowitz DE, Wei C, Hare JM. Cardiac myocyte apoptosis is associated with increased DNA damage and decreased survival in murine models of obesity. Circ Res. 2006 Jan 6;98(1):119-24. Epub 2005 Dec 8. PubMed PMID: 16339484.
 
 
Yamamori T, White AR, Mattagajasingh I, Khanday FA, Haile A, Qi B, Jeon BH, Bugayenko A, Kasuno K, Berkowitz DE, Irani K. P66shc regulates endothelial NO production and endothelium-dependent vasorelaxation: implications for age-associated vascular dysfunction.J Mol Cell Cardiol. 2005 Dec;39(6):992-5. Epub 2005 Oct 19. PubMed PMID: 16242150.
 
 
Jung AS, Harrison R, Lee KH, Genut J, Nyhan D, Brooks-Asplund EM, Shoukas AA, Hare JM, Berkowitz DE. Simulated microgravity produces attenuated baroreflex-mediated pressor, chronotropic, and inotropic responses in mice. Am J Physiol Heart Circ Physiol. 2005 Aug;289(2):H600-7. Epub 2005 Mar 18. PubMed PMID: 15778286.
 
 
Minhas KM, Khan SA, Raju SV, Phan AC, Gonzalez DR, Skaf MW, Lee K, Tejani AD, Saliaris AP, Barouch LA, O'Donnell CP, Emala CW, Berkowitz DE, Hare JM. Leptin repletion restores depressed {beta}-adrenergic contractility in ob/ob mice independently of cardiac hypertrophy.. J Physiol. 2005 Jun 1;565(Pt 2):463-74. Epub 2005 Mar 10. Erratum in: J Physiol. 2005 Aug 1;566(Pt 3):999. Saliaris, Anastasies P [corrected to Saliaris, Anastasios P]. PubMed PMID: 15760936; PubMed Central PMCID: PMC1464532.
 
 
Khan SA, Lee K, Minhas KM, Gonzalez DR, Raju SV, Tejani AD, Li D, Berkowitz DE, Hare JM. Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling. Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15944-8. Epub 2004 Oct 14. PubMed PMID:
15486091; PubMed Central PMCID: PMC528749.
 
 
Jeon BH, Gupta G, Park YC, Qi B, Haile A, Khanday FA, Liu YX, Kim JM, Ozaki M, White AR, Berkowitz DE, Irani K. Apurinic/apyrimidinic endonuclease 1 regulates endothelial NO production and vascular tone. Circ Res. 2004 Oct 29;95(9):902-10. Epub 2004 Oct 7. PubMed PMID: 15472121
 
 
Townsend SA, Jung AS, Hoe YS, Lefkowitz RY, Khan SA, Lemmon CA, Harrison RW, Lee K, Barouch LA, Cotecchia S, Shoukas AA, Nyhan D, Hare JM, Berkowitz DE. Critical role for the alpha-1B adrenergic receptor at the sympathetic neuroeffector junction. Hypertension. 2004 Nov;44(5):776-82. Epub 2004 Oct 4. PubMed PMID: 15466664.
 
 
Jhaveri R, Kim S, White AR, Burke S, Berkowitz DE, Nyhan D. Enhanced vasodilatory responses to milrinone in catecholamine-precontracted small pulmonary arteries.. Anesth Analg. 2004 Jun;98(6):1618-22, table of contents. PubMed PMID: 15155314.
 
 
Berkowitz DE, White R, Li D, Minhas KM, Cernetich A, Kim S, Burke S, Shoukas AA, Nyhan D, Champion HC, Hare JM. Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels.  Circulation. 2003 Oct 21;108(16):2000-6. Epub 2003 Sep 29. PubMed PMID: 14517171.
 
 
Barouch LA, Berkowitz DE, Harrison RW, O'Donnell CP, Hare JM. Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice.. Circulation. 2003 Aug 12;108(6):754-9. Epub 2003 Jul 28. PubMed PMID: 12885755.
 
 
Khan SA, Skaf MW, Harrison RW, Lee K, Minhas KM, Kumar A, Fradley M, Shoukas AA, Berkowitz DE, Hare JM. Nitric oxide regulation of myocardial contractility and calcium cycling: independent impact of neuronal and endothelial nitric oxide synthases.Circ Res. 2003 Jun 27;92(12):1322-9. Epub 2003 May 22. PubMed PMID: 12764022.
 
 
Brooks-Asplund EM, Shoukas AA, Kim SY, Burke SA, Berkowitz DE. Estrogen has opposing effects on vascular reactivity in obese, insulin-resistant male Zucker rats.. J Appl Physiol. 2002 May;92(5):2035-44. PubMed PMID: 11960955.
 
 
Barouch LA, Harrison RW, Skaf MW, Rosas GO, Cappola TP, Kobeissi ZA, Hobai IA, Lemmon CA, Burnett AL, O'Rourke B, Rodriguez ER, Huang PL, Lima JA, Berkowitz DE, Hare JM. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature. 2002 Mar 21;416(6878):337-9. PubMed PMID: 11907582.
 
 
Nyhan D, Kim S, Dunbar S, Li D, Shoukas A, Berkowitz DE. Impaired pulmonary artery contractile responses in a rat model of microgravity: role of nitric oxide. J Appl Physiol. 2002 Jan;92(1):33-40. PubMed PMID: 11744640.
 
 
Dunbar SL, Tamhidi L, Berkowitz DE, Shoukas AA. Hindlimb unweighting affects rat vascular capacitance function. Am J Physiol Heart Circ Physiol. 2001 Sep;281(3):H1170-7. PubMed PMID: 11514284.
 
 
Brown DR, Berkowitz DE, Breslow MJ. Weight loss is not associated with hyperleptinemia in humans with pancreatic cancer.J Clin Endocrinol Metab. 2001 Jan;86(1):162-6. PubMed PMID: 11231995.
 
 
Winters B, Mo Z, Brooks-Asplund E, Kim S, Shoukas A, Li D, Nyhan D, Berkowitz DE. Reduction of obesity, as induced by leptin, reverses endothelial dysfunction in obese (Lep(ob)) mice. J Appl Physiol. 2000 Dec;89(6):2382-90. PubMed PMID: 11090593.
 
 
Dunbar SL, Berkowitz DE, Brooks-Asplund EM, Shoukas AA. The effects of hindlimb unweighting on the capacitance of rat small mesenteric veins.  J Appl Physiol. 2000 Nov;89(5):2073-7. PubMed PMID: 11053364.
 
 
Shapiro RE, Winters B, Hales M, Barnett T, Schwinn DA, Flavahan N, Berkowitz DE. Endogenous circulating sympatholytic factor in orthostatic intolerance.  2000 Oct;36(4):553-60. PubMed PMID: 11040235.
 
 
Varghese P, Harrison RW, Lofthouse RA, Georgakopoulos D, Berkowitz DE, Hare JM. beta(3)-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility.  J Clin Invest. 2000 Sep;106(5):697-703. PubMed PMID: 10974023; PubMed Central PMCID: PMC381285.
 
 
Berkowitz DE. Molecular biology in cardiovascular anesthesiology: the brave new frontier.J Cardiothorac Vasc Anesth. 1999 Dec;13(6):744-51. Review. PubMed PMID: 10622662.
 
 
Rudner XL, Berkowitz DE, Booth JV, Funk BL, Cozart KL, D'Amico EB, El-Moalem H, Page SO, Richardson CD, Winters B, Marucci L, Schwinn DA. Subtype specific regulation of human vascular alpha(1)-adrenergic receptors by vessel bed and age.Circulation. 1999 Dec 7;100(23):2336-43. PubMed PMID: 10587338.
 
 
de Ravel TJ, Berkowitz DE, Wagner JM, Jenkins T. Brachydactyly type B with its distinct facies and 'Cooks syndrome' are the same entity.  Clin Dysmorphol. 1999 Jan;8(1):41-5. PubMed PMID: 10327250.
 
 
O'donnell CP, Schaub CD, Haines AS, Berkowitz DE, Tankersley CG, Schwartz AR, Smith PL. Leptin prevents respiratory depression in obesity.  Am J Respir Crit Care Med. 1999 May;159(5 Pt 1):1477-84. PubMed PMID: 10228114.
 
 
Breslow MJ, Min-Lee K, Brown DR, Chacko VP, Palmer D, Berkowitz DE. Effect of leptin deficiency on metabolic rate in ob/ob mice.Am J Physiol. 1999 Mar;276(3 Pt 1):E443-9. PubMed PMID: 10070008.
 
 
Berkowitz DE, Brown D, Lee KM, Emala C, Palmer D, An Y, Breslow M.  Endotoxin-induced alteration in the expression of leptin and beta3-adrenergic receptor in adipose tissue. Am J Physiol. 1998 Jun;274(6 Pt 1):E992-7. PubMed PMID: 9611147.
 
 
Breslow MJ, An Y, Berkowitz DE. Beta-3 adrenoceptor (beta-3AR) expression in leptin treated OB/OB mice.Life Sci. 1997;61(1):59-64. PubMed PMID: 9200670.
 
 
Berkowitz DE, Richardson C, Elliott DA, Leslie JB, Schwinn DA. Hypotension resistant to therapy with alpha receptor agonists complicating cardiopulmonary bypass: lithium as a potential cause.Anesth Analg. 1996 May;82(5):1082-5. PubMed PMID: 8610874.
 
 
Davies MG, Berkowitz DE, Hagen PO. Constitutive nitric oxide synthase is expressed and nitric oxide-mediated relaxation is preserved in retrieved human aortocoronary vein grafts.  J Surg Res. 1995 Jun;58(6):732-8. PubMed PMID: 7540701.
 
 
Berkowitz DE, Nardone NA, Smiley RM, Price DT, Kreutter DK, Fremeau RT, Schwinn DA. Distribution of beta 3-adrenoceptor mRNA in human tissues.1995 Apr 28;289(2):223-8. PubMed PMID: 7621895.
 
 
Berkowitz DE, Price DT, Bello EA, Page SO, Schwinn DA. Localization of messenger RNA for three distinct alpha 2-adrenergic receptor subtypes in human tissues. Evidence for species heterogeneity and implications for human pharmacology.Anesthesiology. 1994 Nov;81(5):1235-44. PubMed PMID: 7978483.
 
 
Price DT, Chari RS, Berkowitz DE, Meyers WC, Schwinn DA. Expression of alpha 1-adrenergic receptor subtype mRNA in rat tissues and human SK-N-MC neuronal cells: implications for alpha 1-adrenergic receptor subtype classification. 1994 Aug;46(2):221-6. PubMed PMID: 8078485.
 
 
Gandhi CR, Berkowitz DE, Watkins WD. Endothelins. Biochemistry and pathophysiologic actions.1994 Apr;80(4):892-905. Review. PubMed PMID: 8024144.
 
 
 
 
 

 
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