Profile

Research in our laboratory focuses on the following areas:
1. Role of the renin-angiotensin-aldosterone system in modulating oxidative stress, inflammation and fibrinolysis.
The renin-angiotensin-aldosterone system (RAAS) is one of the major blood pressure regulating systems in the body. The small peptide angiotensin II, Ang II, raises blood pressure by constricting blood vessels and increasing salt retention, in part by stimulating synthesis of the mineralocorticoid aldosterone. We now understand that the RAAS has other detrimental effects on the blood vessels, heart and kidney. Both Ang II and aldosterone cause inflammation and fibrosis and promote clotting. Studies in our laboratory are examining the mechanisms of these effects.

2. Role of the renin-angiotensin-aldosterone system in regulating glucose homeostasis.
Sixty per cent of Americans are obese and both the activity of the RAAS and inflammation are increased in obesity. Obese individuals are at increased risk for the development of diabetes and hypertension, but drugs that interrupt the RAAS seem to decrease this risk. Studies in our laboratory are helping us to understand the mechanism for this effect so that we may devise better strategies to prevent diabetes.

3. Cardiovascular effects of the kallikrein-kinin system.
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are the two major classes of drugs currently used to interrupt the renin-angiotensin-aldosterone system. ACE inhibitors decrease the formation of Ang II, whereas ARBs block the effect of Ang II at its major receptor. In addition, ACE inhibitors prevent the breakdown of and promote the actions of bradykinin, a peptide in the body that lowers blood pressure. Bradykinin has other beneficial effects, like increasing tissue-type plasminogen activator from the endothelium. Bradykinin can also have detrimental effects, promoting inflammation. The net beneficial or detrimental effect of bradykinin may depend on the health of the blood vessels.

4. Role of arachidonic acid monooxygenases and epoxygenases in the regulation of blood pressure and cardiovascular risk.
Bradykinin exerts its blood pressure lowering effects, in part, through effects on cytochrome P450 (CYP450) epoxygenases that form eicosatetraenoic acids (EETs) from arachidonic acid. EETs relax blood vessels. EETs formed in the kidney also stimulate salt excretion. Animal studies suggest that, in the kidney, EET formation is regulated in part by 20-hydroxyeicosatetraenoic acid 20-HETE, the product of CYP4A11. Research in our laboratory indicates that a loss-of-function variant of the gene encoding CYP4A11 is associated with high blood pressure and progression of renal disease. We are refining our understanding of how these systems regulate blood pressure in humans and how they interact with the RAAS.

5. Contribution of peptidases to angiotensin-converting enzyme (ACE) inhibitor-associated angioedema.
Despite the many beneficial effects of ACE inhibitors, this class of medications can cause swelling of the lips, tongue, or face, a side effect called angioedema. Likely, this side effect results from decreased breakdown of bradykinin and another peptide called substance P. We have determined groups of patients who are at increased risk for angioedema. Studies in our laboratory have identified one pathway involved in angioedema and will allow us to better predict risk and prevent the side effect.

6. Pharmacogenetics of the renin-angiotensin-aldosterone and kallikrein-kinin sytems.
Genetic factors modulate all of the processes described above. One goal of our laboratory is to identify these factors in order to better predict individual responses to drugs such as ACE inhibitors, ARBs, aldosterone receptor blockers and renin inhibitors.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Pharmacogenomics of Off-target ADRs. Garon SL, Pavlos RK, White KD, Brown NJ, Stone CA, Phillips EJ (2017) Br J Clin Pharmacol
    › Primary publication · 28345177 (PubMed)
  2. Effect of bradykinin receptor antagonism on ACE inhibitor-associated angioedema. Straka BT, Ramirez CE, Byrd JB, Stone E, Woodard-Grice A, Nian H, Yu C, Banerji A, Brown NJ (2016) J Allergy Clin Immunol
    › Primary publication · 27913306 (PubMed)
  3. Cardiovascular Disease Risk Factors in Ghana during the Rural-to-Urban Transition: A Cross-Sectional Study. Kodaman N, Aldrich MC, Sobota R, Asselbergs FW, Poku KA, Brown NJ, Moore JH, Williams SM (2016) PLoS One 11(10): e0162753
    › Primary publication · 27732601 (PubMed) · PMC5061429 (PubMed Central)
  4. Plasminogen Activator Inhibitor-1 and Diagnosis of the Metabolic Syndrome in a West African Population. Kodaman N, Aldrich MC, Sobota R, Asselbergs FW, Brown NJ, Moore JH, Williams SM (2016) J Am Heart Assoc 5(10)
    › Primary publication · 27697752 (PubMed) · PMC5121488 (PubMed Central)
  5. Examining EXAMINE for an Interaction With Angiotensin-Converting Enzyme Inhibition. Wilson JR, Brown NJ (2016) Hypertension 68(3): 549-51
    › Primary publication · 27480841 (PubMed) · PMC4982800 (PubMed Central)
  6. Epoxyeicosatrienoic acids and glucose homeostasis in mice and men. Luther JM, Brown NJ (2016) Prostaglandins Other Lipid Mediat : 2-7
    › Primary publication · 27448715 (PubMed) · PMC5035218 (PubMed Central)
  7. Response by Hubers and Brown to Letter Regarding Article, "Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition". Hubers SA, Brown NJ (2016) Circulation 134(3): e11-2
    › Primary publication · 27436883 (PubMed) · PMC4957697 (PubMed Central)
  8. Statins to Reduce Acute Kidney Injury After Cardiac Surgery--Reply. Billings FT, Brown NJ (2016) JAMA 316(3): 349-50
    › Primary publication · 27434456 (PubMed)
  9. Selective serotonin reuptake inhibitor exposure constricts the mouse ductus arteriosus in utero. Hooper CW, Delaney C, Streeter T, Yarboro MT, Poole S, Brown N, Slaughter JC, Cotton RB, Reese J, Shelton EL (2016) Am J Physiol Heart Circ Physiol 311(3): H572-81
    › Primary publication · 27371685 (PubMed) · PMC5142184 (PubMed Central)
  10. Mitochondrial dysfunction and oxidative stress in patients with chronic kidney disease. Gamboa JL, Billings FT, Bojanowski MT, Gilliam LA, Yu C, Roshanravan B, Roberts LJ, Himmelfarb J, Ikizler TA, Brown NJ (2016) Physiol Rep 4(9)
    › Primary publication · 27162261 (PubMed) · PMC4873632 (PubMed Central)
  11. Comparative effects of immediate-release and extended-release aspirin on basal and bradykinin-stimulated excretion of thromboxane and prostacyclin metabolites. Gamboa JL, Devin JK, Ramirez CE, Yu C, Nian H, Lee RH, Brown NJ (2016) Pharmacol Res Perspect 4(2): e00221
    › Primary publication · 27069632 (PubMed) · PMC4804312 (PubMed Central)
  12. B-Type Natriuretic Peptide, Aldosterone, and Fluid Management in ARDS. Semler MW, Marney AM, Rice TW, Nian H, Yu C, Wheeler AP, Brown NJ, NIH NHLBI ARDS Network (2016) Chest 150(1): 102-11
    › Primary publication · 27018313 (PubMed) · PMC4980545 (PubMed Central)
  13. Heart failure event definitions in drug trials in patients with type 2 diabetes. Sharma A, Bhatt DL, Calvo G, Brown NJ, Zannad F, Mentz RJ (2016) Lancet Diabetes Endocrinol 4(4): 294-6
    › Primary publication · 27016320 (PubMed) · PMC5221765 (PubMed Central)
  14. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition. Hubers SA, Brown NJ (2016) Circulation 133(11): 1115-24
    › Primary publication · 26976916 (PubMed) · PMC4800749 (PubMed Central)
  15. High-Dose Perioperative Atorvastatin and Acute Kidney Injury Following Cardiac Surgery: A Randomized Clinical Trial. Billings FT, Hendricks PA, Schildcrout JS, Shi Y, Petracek MR, Byrne JG, Brown NJ (2016) JAMA 315(9): 877-88
    › Primary publication · 26906014 (PubMed) · PMC4843765 (PubMed Central)
  16. High-Throughput Screening of Myometrial Calcium-Mobilization to Identify Modulators of Uterine Contractility. Herington JL, Swale DR, Brown N, Shelton EL, Choi H, Williams CH, Hong CC, Paria BC, Denton JS, Reese J (2015) PLoS One 10(11): e0143243
    › Primary publication · 26600013 (PubMed) · PMC4658040 (PubMed Central)
  17. Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial. Ramirez CE, Nian H, Yu C, Gamboa JL, Luther JM, Brown NJ, Shibao CA (2015) J Clin Endocrinol Metab 100(12): 4533-40
    › Primary publication · 26580240 (PubMed) · PMC4667163 (PubMed Central)
  18. Angiotensin converting enzyme inhibition increases ADMA concentration in patients on maintenance hemodialysis--a randomized cross-over study. Gamboa JL, Pretorius M, Sprinkel KC, Brown NJ, Ikizler TA (2015) BMC Nephrol : 167
    › Primary publication · 26494370 (PubMed) · PMC4618919 (PubMed Central)
  19. A prevalent caveolin-1 gene variant is associated with the metabolic syndrome in Caucasians and Hispanics. Baudrand R, Goodarzi MO, Vaidya A, Underwood PC, Williams JS, Jeunemaitre X, Hopkins PN, Brown N, Raby BA, Lasky-Su J, Adler GK, Cui J, Guo X, Taylor KD, Chen YD, Xiang A, Raffel LJ, Buchanan TA, Rotter JI, Williams GH, Pojoga LH (2015) Metabolism 64(12): 1674-81
    › Primary publication · 26475177 (PubMed) · PMC4641791 (PubMed Central)
  20. Genetics of Plasminogen Activator Inhibitor-1 (PAI-1) in a Ghanaian Population. White MJ, Kodaman NM, Harder RH, Asselbergs FW, Vaughan DE, Brown NJ, Moore JH, Williams SM (2015) PLoS One 10(8): e0136379
    › Primary publication · 26322636 (PubMed) · PMC4556460 (PubMed Central)
  21. Hypertension is associated with preamyloid oligomers in human atrium: a missing link in atrial pathophysiology? Sidorova TN, Mace LC, Wells KS, Yermalitskaya LV, Su PF, Shyr Y, Atkinson JB, Fogo AB, Prinsen JK, Byrne JG, Petracek MR, Greelish JP, Hoff SJ, Ball SK, Glabe CG, Brown NJ, Barnett JV, Murray KT (2014) J Am Heart Assoc 3(6): e001384
    › Primary publication · 25468655 (PubMed) · PMC4338732 (PubMed Central)
  22. Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans. Ramirez CE, Shuey MM, Milne GL, Gilbert K, Hui N, Yu C, Luther JM, Brown NJ (2014) Prostaglandins Other Lipid Mediat : 38-44
    › Primary publication · 25173047 (PubMed) · PMC4253976 (PubMed Central)
  23. Dipeptidyl-peptidase 4 inhibition and the vascular effects of glucagon-like peptide-1 and brain natriuretic peptide in the human forearm. Devin JK, Pretorius M, Nian H, Yu C, Billings FT, Brown NJ (2014) J Am Heart Assoc 3(4)
    › Primary publication · 25158865 (PubMed) · PMC4310400 (PubMed Central)
  24. Genetic variation in CYP4A11 and blood pressure response to mineralocorticoid receptor antagonism or ENaC inhibition: an exploratory pilot study in African Americans. Laffer CL, Elijovich F, Eckert GJ, Tu W, Pratt JH, Brown NJ (2014) J Am Soc Hypertens 8(7): 475-80
    › Primary publication · 25064769 (PubMed) · PMC4115247 (PubMed Central)
  25. Dietary sodium restriction decreases insulin secretion without affecting insulin sensitivity in humans. Luther JM, Byrne LM, Yu C, Wang TJ, Brown NJ (2014) J Clin Endocrinol Metab 99(10): E1895-902
    › Primary publication · 25029426 (PubMed) · PMC4184066 (PubMed Central)
  26. Quantitative Imaging of Preamyloid Oligomers, a Novel Structural Abnormality, in Human Atrial Samples. Sidorova TN, Mace LC, Wells KS, Yermalitskaya LV, Su PF, Shyr Y, Byrne JG, Petracek MR, Greelish JP, Hoff SJ, Ball SK, Glabe CG, Brown NJ, Barnett JV, Murray KT (2014) J Histochem Cytochem 62(7): 479-87
    › Primary publication · 24789805 (PubMed) · PMC4072180 (PubMed Central)
  27. Changes in B-type natriuretic peptide and BMI following Roux-en-Y gastric bypass surgery. Marney AM, Brown NJ, Tamboli R, Abumrad N (2014) Diabetes Care 37(4): e70-1
    › Primary publication · 24652734 (PubMed) · PMC3964493 (PubMed Central)
  28. Pollen count and presentation of angiotensin-converting enzyme inhibitor-associated angioedema. Straka B, Nian H, Sloan C, Byrd JB, Woodard-Grice A, Yu C, Stone E, Steven G, Hartert T, Teo KK, Pare G, McCarty CA, Brown NJ (2013) J Allergy Clin Immunol Pract 1(5): 468-73.e1-4
    › Primary publication · 24565618 (PubMed) · PMC4042396 (PubMed Central)
  29. Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition. Devin JK, Pretorius M, Nian H, Yu C, Billings FT, Brown NJ (2014) Hypertension 63(5): 951-7
    › Primary publication · 24516103 (PubMed) · PMC3984385 (PubMed Central)