Professor and Research Cluster Coordinator
Department: Pharmacology, Physiology and Toxicology
Adjunct Professor in Cardiology Department (Medicine)
Office: BBSC 435-S | Laboratory: BBSC 412
Phone: (304) 696-7321
Research Interests – Projects in Progress
Project I: Diet, exercise & obesity drugs on cardiometabolic endpoints
Obesity is on the rise within the United States as well as in a number of other industrialized nations, resulting in increased risk to cardiovascular diseases and diabetes. Two-thirds of adults living within the U.S. are categorized as overweight or obese. Changes in lifestyle (diet and exercise) can help to reduce obesity incidence. Oxidative stress, which is an imbalance between the production of oxygen (or nitrogen) derived free radicals and cell’s antioxidant defense, plays a role in several diseases including obesity. We have shown oxidants such as hydrogen peroxide (H2O2) to induce inflammation and alter adipose differentiation (http://dx.doi.org/10.1089%2Fjmf.2008.0230). We have also shown that the beneficial effects of exercise in lowering atherosclerotic lesions in mice is by upregulating antioxidant enzymes such as catalase (quencher of H2O2) in the arteries (Fig. 1) (http://www.ncbi.nlm.nih.gov/pubmed/11597945?dopt=Abstract#). These and several of our other studies revealed the importance of catalase as an important intermediate in defending the cell against oxidative stress mediated damage. To test the role of this enzyme and oxidative stress in cardiovascular disease and obesity, we generated animal models that express either high levels of catalase in a normal background (catalase transgenic mice) or express high levels of catalase in an obese background (Cat tg x Ob/Ob hybrid mice-Bob-Cat). We are currently exploring the effects of various diets (high fat, high omega-3 rich diets etc) and exercise on cardiometabolic endpoints using these mouse models. In addition, we plan to study the effects of currently available obesity drugs in these mouse models (Fig. 2).
The cardiometabolic endpoints routinely measured includes: (i) lipids and lipoproteins (ii) systemic inflammation (iii) blood pressure, endothelial function (iv) insulin resistance (v) body fat and adipose function (vi) appetite regulation (leptin-hypothalamus) and others. ECHO-MRI, CLAMS, rodent treadmills, rodent ultrasound, next generation sequencing, miRNA microarray, Luminex technology, Ingenuity pathway analysis etc are some of the techniques that is used in our studies.
Project II – epicardial fat and vascular cross talk
Adipose tissue-vascular crosstalk: Obesity is a worldwide public health concern that predisposes individuals to increased risk to cardiovascular disease (CVD) and Type 2 diabetes. West Virginia has the second largest number of people with obesity in the United States. Increase in visceral/abdominal adiposity is a hallmark for obesity. However, increase in ectopic fat (deposition of fat in non-adipose tissue) is correlated with obesity and is also a marker for future cardiovascular events. Aging, an independent risk factor for CVD, results in adipose dysfunction. Studies in our laboratory are investigating the effect of aging and obesity on the distribution and function of epicardial/perivascular fat (the fat that surrounds the heart and the coronaries) in animal models and humans with coronary artery disease. We are interested in studying the role of microRNA and epigenetic pathways in aging related adipose dysfunction.
Aging, an independent risk factor for CVD, results in changes in adipose mass and function. We have previously shown sex differences in epicardial fat biomarkers with aging (http://dx.doi.org/10.1016%2Fj.atherosclerosis.2010.06.044) which may be reflective of the changes in cardiac and vascular function observed with old age. These differences were attributed to the loss of microRNA regulation (miRNA editing) of adipose derived stem cell function with aging (Fig. 5).
Studies in our laboratory are investigating the role of epicardial/perivascular fat (the fat that surrounds the heart and the coronaries) in risk to cardiovascular diseases in animal models and humans with coronary artery disease (CAD). We are interested in also investigating the role of microRNA and epigenetic pathways in adipose dysfunction. Epicardial fat obtained from animal models of obesity or cardiovascular disease or patients with and without coronary artery disease (in collaboration with Department of Cardiology & Thoracic Surgery) are being used for studying biomarkers including miRNA and compared to other fat tissues such as subcutaneous fat. Epicardial fat-vasculature cross talk studies are being conducted using animal models and ex-vivo cell culture models.
Project III – epigenetics in endometriosis and ovarian cancer
Endometriosis is a reproductive disorder affecting about 10% of young women. The classic symptoms are infertility and chronic pain of various forms. Typically this pain is treated with non-steroidal anti-inflammatory drugs (NSAIDs), or with drugs that address the hormonal aspects of the disorder. Research from our laboratory over the past 20 years has shown the importance of oxidative stress in the etiology of both endometriosis and its associated pain (Ann N Y Acad Sci. 2002 Mar;955:183-98). Our clinical studies have shown the beneficial effects of antioxidant therapy (Vitamin E & C) in lowering the pain associated with endometriosis (Transl Res. 2013 Mar;161(3):189-95). Our laboratory in collaboration with the Department of Obstetrics and Gynecology, Marshall University Joan C. Edwards School of Medicine, is currently working to better understand the mechanisms behind endometriosis-associated pain with the hope of uncovering more effective treatment. We are using novel techniques in the fields of oxidative stress and epigenetics to produce new therapeutic options (Fig. 6). Epigenetics encompasses heritable changes in gene and also involves studying the human micronome. Most recently, we presented our research findings on both microRNA and oxidative stress at the World Congress on Endometriosis in Brazil (click HERE for story).
Endometriosis increases risk to ovarian cancer. In our laboratory we are studying the role of peritoneal microenvironment on endometriosis related ovarian cancer. We will investigate epigenetic pathways in this link between endometriosis and ovarian cancer (Fig. 7).
Translational Studies in Progress
- Epicardial Fat Biomarkers: WV-Appalachian Heart Study. In collaboration with Department of Medicine (Cardiology) and Department of Cardiothoracic Surgery, St. Mary’s Heart Center, Huntington, WV.
- Epigenetics, Oxidative Stress and Endometriosis associated pain: In collaboration with Department of Gynecology and Obstetrics, Cabell Huntington Hospital, Huntington, WV.
- MiRNA & Technology Based Intervention In Diabetic Patients (ADVANCE Clinical Trial): In collaboration with Department of Endocrinology (Medicine) and Appalachian Translational Research Network
- MiRNA & Type 1 Diabetes: In collaboration with Department of Endocrinology (Medicine).
- Salisbury TB, Tomblin JK, Primerano DA, Boskovic G, Fan J, Memmi I, Fletcher J, Santanam N, Hurn E, Morris GZ, Denvir J.Endogenous aryl hydrocarbon receptor promotes basal and inducible expression of tumor necrosis factor target genes in MCF-7 cancer cells. Biochem Pharmacol. 2014 Jun 24. pii: S0006-2952(14)00358-X. doi: 10.1016/j.bcp.2014.06.015
- Salisbury TB, Morris G, Tomblin J, Chaudry A, Cook C, Santanam N. Aryl hydrocarbon receptor ligands inhibit IGF-II and adipokine stimulated breast cancer cell proliferation (2013) ISRN Endocrinology. Volume 2013, Article ID 104850, 9 pages.
- Fei J, Holly Tamski, Carla Cook and Santanam N. MicroRNA regulation of adipose derived stem cell in Aging rats. (2013) PLoS One, 8(3):e59238
- Garelnabi, M, Jin J, F. Chai, Lor, K, Santanam N. The paradox of ApoA5 modulation of triglycerides: evidences from clinical and basic studies. (2013) Clin Biochem. 46(1-2):12-9
- Santanam, N, Thornhill BA, Lau JK, Brown KC, Crabtree CK, Carla C, Dasgupta P. Nicotinic Acetylcholine receptor signaling in atherogenesis. (2012) Atherosclerosis. 225(2):264-73
- Penumetcha M and Santanam N. Nutraceuticals as Ligands of PPARγ. (2012) PPAR Research (Special Issue) (Invited review) 2012: 858352
- Santanam N, Kavatradze N, Murphy A, Dominguez C and S. Parthasarathy. Antioxidant supplementation reduces endometriosis related pelvic pain in humans. (2012) Translational Research. 159,1-7
- Valentovic M and Santanam N. Nutrition, Oxidative Stress and Cancer. Chapter 7, pp77-86 In. Nutrition and cancer. From Epidemiology to Biology (2012) Editors. Pier Paolo Claudio and Richard M. Niles. Bentham Science Publishers
- Fei J, Cook C and Santanam N. ω-6 lipids regulate PPAR turnover via reciprocal switch between PGC-1alpha and ubiquitination. (2012) Atherosclerosis, 222: 395-401.
- Garelnabi MO, Veledar E, White-Welkely J, Santanam N, Weintraub W, Abramson, J, Parthasarathy S. Vitamin E differentially affects the short term exercise induced changes in oxidative Stress, lipids, and inflammatory markers: A double blind randomized controlled trial. (2011) Nutrition, Metabolism & Cardiovascular Diseases). PMID: 21782401
- Wu M, Wan B, Fei J, Santanam N and Blough E. Important roles of Akt/PkB signaling in aging process. (2010) Frontiers in Bioscience S2, 1169:1188.
- Parthasarathy S, Raghavamenon A, Garelnabi MO, Santanam, N. Oxidized Low-density Lipoprotein. In. Free Radicals and Antioxidant Protocols. Methods in Molecular Biology.610: (2010), 403-17. Editors. Rao M. U, Subramanyam N. M, William A. P and Narasimham L. P. Springer Link beta.
Nalini Santanam, PhD, MPH – Professor
Kristeena Ray Wright – PhD Candidate
Debbie Amos – PhD Student
Akhil Gudivada – Undergraduate Student