Scott Levick

Organization:

West Virginia University School of Medicine

Department:

Physiology, Pharmacology & Toxicology

Classification:

Faculty

1. Levick S, Fenning A, Brown L. Increased calcium influx mediates increased cardiac stiffness in hyperthyroid rats. Cell Biochem Biophys. 2005;43:53-60.

2. Allan A, Fenning A, Levick S, Hoey A, Brown L. Reversal of cardiac dysfunction by selective ET-A receptor antagonism. Br J Pharmacol. 2005;146:846-53.

3. Loch D, Levick S, Hoey A, Brown L. Rosuvastatin attenuates hypertension-induced cardiovascular remodeling without affecting blood pressure in DOCA-salt hypertensive rats. J Cardiovasc Pharmacol. 2006;47:396-404.

4. Levick S, Loch D, Rolfe B, Reid R, Fairlie D, Taylor S, Brown L. Antifibrotic activity of an inhibitor of group IIA secretory phospholipase A2 in young spontaneously hypertensive rats. J Immunol. 2006;176:7000-7.

5. Brower GL, Levick SP, Janicki JS. Inhibition of matrix metalloproteinase activity by ACE inhibitors prevents left ventricular remodeling in a rat model of heart failure. Am J Physiol Heart Circ Physiol. 2007;292:H3057-64.

6. Murray DB, Gardner JD, Levick SP, Brower GL, Morgan LM, Janicki JS. Response of cardiac mast cells to atrial natriuretic peptide. Am J Physiol Heart Circ Physiol. 2007;293:H1216-22.

7. Morgan LG, Levick SP, Murray DB, Forman MF, Brower GL, Janicki JS. A novel technique for isolating functional mast cells from the heart. Inflamm Res. 2008;57:241-6.

8. Levick SP, Gardner JD, Holland M, Hauer-Jensen M, Janicki JS, Brower GL. Protection from adverse myocardial remodeling secondary to chronic volume overload in mast cell deficient rats. J Mol Cell Cardiol. 2008;45:56-61.

9. Levick SP, McLarty JL, Murray DB, Freeman RM, Carver WE, Brower GL. Cardiac mast cells mediate left ventricular fibrosis in the hypertensive rat heart. Hypertension. 2009;53:1041-7.

10. Jobe LJ, Melendez GC, Levick SP, Du Y, Brower GL, Janicki JS. TNF-alpha inhibition attenuates adverse myocardial remodeling in a rat model of volume overload. Am J Physiol Heart Circ Physiol. 2009;297:H1462-8.

11. Levick SP, Murray DB, Janicki JS, Brower GL. Sympathetic nervous system modulation of inflammation and remodeling in the hypertensive heart. Hypertension. 2010;55:270-6.

12. Murray DB, Levick SP, Brower GL, Janicki JS. Inhibition of matrix metalloproteinase activity prevents increases in myocardial tumor necrosis factor-alpha. J Mol Cell Cardiol. 2010;49:245-50.

13. Meléndez GC, McLarty JL, Levick SP, Du Y, Janicki JS, Brower GL. Interleukin 6 mediates myocardial fibrosis, concentric hypertrophy, and diastolic dysfunction in rats. Hypertension. 2010;56:225-31. (selected for Editorial Comment)

14. Melendez GC, Voloshenyuk TG, McLarty JL, Levick SP, Brower GL. Oxidative stress mediated cardiac mast cell degranulation. Toxicological and Environmental Chemistry. 2010;92:1393-3101.

15. Chan V, Fenning A, Levick SP, Loch D, Chunduri P, Iyera A, Teoa YL, Hoey A, Wilson K, Burstow D, Brown L. Cardiovascular changes during maturation and ageing in male and female spontaneously hypertensive rats. J Cardiovasc Pharmacol. 2011;57:469-78.

16. McLarty JL, Melendez GC, Brower GL, Janicki JS, Levick SP. Tryptase/Protease-activated receptor 2 interactions induce selective mitogen-activated protein kinase signaling and collagen synthesis by cardiac fibroblasts. Hypertension. 2011;58:264-70. (selected for Editorial Comment)

17. Melendez GC, Li J, Law BA, Janicki JS, Supowit SC, Levick SP. Substance P induces adverse myocardial remodeling via a mechanism involving cardiac mast cells. Cardiovasc Res, 2011;92:420-9. (selected for European Society of Cardiology special issue translated to Russian)

18. McLarty JL, Melendez GC, Spencer WJ, Levick SP, Brower GL, Janicki JS. Isolation of Functional Cardiac Immune Cells. J Vis Exp. 2011(58).

19. Lu H, Melendez GC, Levick SP, Janicki JS. Prevention of adverse cardiac remodeling to volume overload in female rats is the result of an estrogen-altered mast cell phenotype. Am J Physiol Heart Circ Physiol. 2012;302:H811-H817.

20. McLarty JL, Melendez GC, Levick SP, Bennett S, Sabo-Attwood T, Brower GL, Janicki JS. Estrogenic modulation of inflammation-related genes in male rats following volume overload. Physiol Genomics, 2012;44:362-373.

21. Law BA, Levick SP, Carver WE. Alterations in cardiac structure and function in a murine model of chronic alcohol consumption. Microsc Microanal, 2012;18:453-461.

22. Li J, Lu H, Plante E, Meléndez GC, Levick SP, Janicki JS. Stem cell factor is responsible for the rapid response in mature mast cell density in the acutely stressed heart. J Mol Cell Cardiol. 2012;53:469-474.

23. Li J, Levick SP, Janicki JS, Dipette DJ, Supowit SC. Alpha-calcitonin gene-related peptide is protective against pressure overload-induced heart failure. Regulatory Peptides, 2013;185:20-28.

24. McLarty JL, Li J, Levick SP, Janicki JS. Estrogen modulates the influence of cardiac inflammatory cells on cardiac fibroblast function. J Inflamm Res, 2013;6:99-108.

25. Dehlin HM, Manteufel EJ, Monroe AL, Reimer MH, Levick SP. Substance P acting via the neurokinin-1 receptor regulates adverse myocardial remodeling in a rat model of hypertension. Int J Cardiol, 2013;168:4643-4651.

26. Melendez GC, Manteufel EJ, Dehlin HM, Register TC, Levick SP. Non-human primate and rat cardiac fibroblasts show similar extracellular matrix-related and cellular adhesion gene responses to substance P. Heart, Lung, and Circulation, 2015;24:395-403.

27. Jubair S, Li J, Dehlin HM, Manteufel EJ, Levick SP, Janicki JS. Substance P induces cardioprotection from ischemia via activation of AKT. Am J Physiol: Heart Circ Physiol, 2015;309:H676-H684.

28. Brower GL, Levick SP, Janicki JS. Differential effects of prevention and reversal treatment with lisinopril on left ventricular remodeling in a rat model of heart failure. Heart, Lung, and Circulation, 2015;24:919-924.

29. Li J, Jubair S, Levick SP, Janicki JS. The autocrine role of tryptase in pressure overload-induced mast cell activation, chymase release and cardiac fibrosis. Int J Cardiol: Metabolic & Endocrine, 2016;10:16-23.

30. Sharma A, Khan A-H, Levick SP, Sing K, Lee S, Hammock BD, Imig JD. Novel omega-3 fatty acid epoxygenase metabolite reduces kidney fibrosis. Int J Mol Sci, 2016;17:751.

31. Levick SP, Soto-Pantoja DR, Bradshaw TW, Hundley WG, Widiapradja A, Manteufel EJ, Bi J, Meléndez GC. Doxorubicin-induced myocardial fibrosis involves the neurokinin-1 receptor and direct effects on cardiac fibroblasts. Heart, Lung and Circulation, 2019;28:1598-1605 (selected as best scientific article for 2019).

32. Levick SP, Brower GL, Janicki JS. Substance P-mediated cardiac mast cell activation and its modulation: An in vitro study. Neuropeptides, 2019;74:52-59.

33. Widiapradja A, Dehlin HM, Manteufel EJ, Pena J, Goldspink PH, Sharma A, Imig J, Lu B, Levick SP. Regulation of cardiac mast cell maturation and function by the neurokinin-1 receptor in the fibrotic heart. Scientific Reports, 2019;9:11004.

34. McCaffery SL, Lim G, Bullock M, Kasparian AO, Clifton-Bligh R, Campbell WB, Widiapradja A, Levick SP. The histamine 3 receptor is expressed in the heart and its activation opposes adverse cardiac remodeling in the angiotensin II mouse model. Int J Mol Sci, 2020;21:9757 (Invited Article - Special Issue: Extracellular Matrix in Heart Disease).

35. Widiapradja A, Kasparian AO, McCaffrey SL, Kolb L, Imig J, Melendez GC, Levick SP. Replacement of lost substance P reduces fibrosis in the diabetic heart by preventing adverse fibroblast and macrophage phenotype changes. Cells, 2021;10:2659.

My laboratory is interested in the mechanisms that underlie adverse cardiac remodeling leading to heart failure. We are particularly focused on cardiac fibrosis, a condition of excess extracellular matrix production that has important consequences for cardiac function. Current projects involve investigations into the contribution of neuropeptides and inflammatory cells to this process.

1. Replacement substance P as a treatment for diabetic fibrosis

2. The role of the neurokinin-1 receptor in the development of cardiac fibrosis and hypertrophy

3. Histamine 3 receptor activation as a therapy for adverse cardiac remodeling

4. Catestatin as an anti-fibrotic molecule in the heart

1. Using a mouse model of type 2 diabetes, we have established that the loss of the neuropeptide substance P (SP) that occurs in diabetes, predisposes the heart to developing fibrosis. As such, replacement SP can reduce diabetic fibrosis. This appears to be by direct actions of SP to oppose high glucose-induced fibroblast conversion to the more active myofibroblast phenotype, as well as by opposing the pro-inflammatory M1 macrophage phenotype and promoting a more beneficial M1 to M2 macrophage ratio. The ongoing aims of this project are to: 1) identify the neurokinin receptor mediating the protective actions of SP in the diabetic heart; 2) determine the extent to which the ability of SP to prevent adverse fibroblast and macrophage phenotype changes in response to high glucose involves modulating cell oxidative status; and 3) determine if there are sex differences in response to the loss of SP in diabetes, and to replacement SP.

2. We have demonstrated the contribution of the neurokinin-1 receptor (NK-1R) to cardiac fibrosis in several disease etiologies, including hypertension and chemotherapy-induced cardiotoxicity. This involves maturation of mast cells via NK-1R mediated production of stem cell factor, regulation of endothelin-1 levels, as well as levels regulation of the ETA receptor. The NK-1R also appears to be important in pathological hypertrophy of the heart. This project will focus on the concept that the NK-1R acts as a molecular switch that when chronically activated stimulates pathways that promote pathological hypertrophy. This project also involves the concept that the Tac1 gene acts as a molecular sensor of hemodynamic load that initiates pathological cardiac hypertrophy.

3. We recently identified transcript for the histamine 3 receptor (H3R) in the normal mouse heart. However, H3R protein could only be detected in the diseased heart. Treatment of mice with the H3R agonist imetit reduced cardiac hypertrophy, fibrosis, and inflammation. This project now aims to clearly identify the cardiac cells that possess the H3R in disease, and to understand the mechanisms by which H3R activation improves cardiac structure and function, including effects on fibroblast, macrophage, and mast cell phenotype.

4. Catestatin is one of seven known peptides that are derived from the propeptide chromogranin A. We have determined that there is a loss of catestatin (but not chromogranin A) in the hypertensive heart, and that restoration of catestatin can prevent fibrosis from occurring in the hypertensive heart. Catestatin exerts effects by blocking nicotinic receptors and hence preventing the release of norepinephrine. However, this is not the mechanism by which catestatin inhibits isolated cardiac fibroblasts from converting to myofibroblasts. This project has many possible directions including identification of a receptor for catestatin, determining whether catestatin modulates inflammation, identification of signaling pathways induced by catestatin, as well as regulation of chromogranin A cleavage and hence production of catestatin.

 

Techniques

• Animal models of cardiac disease (diabetes, hypertension, ischemia)
• Conditional knockout mouse models
• Physiological assessment of cardiac structure and function (Echocardiography, pressure-volume catheterization, isolated heart)
• Primary cell cultures (cardiac fibroblasts, mast cells, macrophages, endothelial cells)
• CRISPR
• Molecular biology, biochemical assays
• Histology, immunolabeling
• Translational studies