Department of Internal Medicine (Cardiology), School of Medicine
Department of Pharmacology, School of Medicine
Inflammation, the Cardiovascular System and Dementia
My research focuses on three areas at this time: heart failure, aging and dementia. Heart failure is a significant cause of morbidity and mortality in our country, and although we have developed devices and some drug treatment, our ability to slow or halt the progression of the disease is limited. Most therapy for heart failure is based on physiology, and attempts to address heart failure associated changes have been disappointing, especially anti-TNF therapy, which worked wonderfully in mice, but made humans somewhat worse. Oddly other anti-TNF treatment for inflammatory diseases, such as rheumatoid arthritis, has worked quite well.
I am just completing a basic study of heart failure treatment in a rat model of high left anterior descending coronary ligation, which produces a large infarct and heart failure by nine weeks. We found that heat shock protein (HSP) 60, one of the protective heat shock proteins, was more than doubled in both human and rat ischemic heart failure (L.Lin et al. Am.J.Physiology 2007). We further found that HSP60 localized to the surface of cardiac myocytes in ischemic heart failure, and the presence of HSP60 correlated with increased activation of apoptosis, which leads to cell death. In a separate study we demonstrated that extracellular HSP60 activated the innate immune system by binding to toll-like receptor (TLR) 4 on cardiac myocytes. This led in cell culture to cardiac myocyte death by apoptosis. It turned out that HSP60 activated TLR4 leading to activation of NFkB, a pro-inflammatory mediator, which led to increased production of TNF, which was released, killing the cell and/or the neighboring cells (SC Kim 2009, Circ.Res). The next step was to inhibit TLR4 and see if we could mitigate the course of CHF in our rat model. A manuscript reporting our results must be reviewed by the company that supplied the investigational drug prior to publication.
The second project we are working on is using exosomes as a potential cardiac biopsy to assess heart failure. Exosomes are small lipid vesicles (50-100 nm in diameter), which are released by many if not all cells. We are developing a mechanism to purify heart specific exosomes from a serum sample. Exosomes form from an invagination of the cell membrane (called the multi-vesicular body or MVB), which then itself has multiple invaginations, which are exosomes. The outer surface of the exosome is derived from the outer surface of the cell. We will apply this to evaluating patients with heart failure. Each exosome is a little bite of cell membrane and cell contents. The exosome can provide much more useful information than the cardiac biopsy, which had sampling issues and also is quite invasive. Exosomes have the ability to provide new information about the progression of heart failure, which can potentially lead to new therapies.
My third project relates to the impact of aging and cell senescence on the blood brain barrier and the development of dementia. I am collaborating with an expert on the blood brain barrier and a neuroscientist, plus I have two neurologists with interest in Alzheimer's, as consultants. This project is quite exciting, and we all looking forward to finishing the experimental work we have started. A revised grant received a good score at the NIA. The proposed work has the potential to provide new insights into dementia.In
Grad Group Affiliations
- Biochemistry, Molecular, Cellular and Developmental Biology
- Molecular, Cellular and Integrative Physiology
- Pharmacology and Toxicology (PTX)
Specialties / Focus
- Cardiorespiratory Physiology
- Cellular Physiology
- Cellular Responses to Toxins and Stress
- Molecular Physiology
- CLH 230 Molecular Mechanisms of Disease: Congestive Heart Failure, Winter
- Molecular and Cellular Cardiology
- Yun Lin, Ph.D., postdoc, Lily Lee, research assistant
Honors and Awards
- Vice Chancellor's Faculty Award for Excellence and Achievement, University of California, Davis 2007
- Albrecht Fleckenstein Memorial Award for Distinguished Contribution to Basic Research, International Academy of Cardiology, 2013
- Distinguished Fellowship Award, International Academy of Cardiology, 2015
- International Society for Heart Research
- Fellow, American Physiological Society
- Fellow, American Heart Association
- 1974 BA Biology, magna cum laude Harvard University
- 1979 MD Medicine Yale
Poe, A.J. and Knowlton, A.A.(2017) Exosomes as agents of change in the cardiovascular system. J Mol Cell Cardiol. 111:40-50.
Knowlton, A.A. (2017) Paying for the Tolls: The High Cost of the Innate Immune System for the Cardiac Myocytes, in The Immunology of Cardiovascular Homeostasis and Pathology, Susanne Settler and Teresa Kennedy-Lydon, editors, Springer, Advances in Experimental Medicine and Biology Series. p. 17-34.
Chongxiu Sun1, S. I. Simon, G. A. Foster, C. E. Radecke, H.T. Hwang, X. Zhang, B. D. Hammock, N. Chiamvimonvat, A. A. Knowlton.(2016) 11,12-Epoxyecosatrienoic Acids Mitigate Endothelial Dysfunction Associated with Estrogen Loss and Aging: Role of Membrane Depolarization. J. Mol Cell Cardiol 94:180-188.
Heiserman, J.P., L. Chen, BS Kim, S.C. Kim, A. L. Tran, N. Siebenborn, A.A. Knowlton. (2015) TLR4 Mutation and HSP60-Induced Cell Death in Adult Mouse Cardiac Myocytes. Cell Stress and Chaperones 20(3):527-535.
Knowlton, A. A., L. Chen and Z. A. Malik (2014) Heart Failure and Mitochondrial Dysfunction: The Role of Mitochondrial Fission/Fusion Abnormalities and New Therapeutic Strategies. Journal of Cardiovascular Pharmacology 63:196-206. Invited review. PMID: 23884159.
Tingting Liu, Le Chen, Eun Jung Kim, Diana Tran, Brett S. Phinney, Anne A. Knowlton. (2014) Mitochondrial Functional and Proteomic Changes in Ischemic Heart failure. Life Sciences 101:27-36.
Malik, Z., K.S. Kott, A.J. Poe, T. Kuo, L. Chen, K. W. Ferrara and A.A. Knowlton. (2013) Cardiac Myocyte Exosomes: Stability, HSP60 and Proteomics. Am. J. Physiol. 304(7):H954-65.
Knowlton, A.A. and A.R. Lee (2012) Estrogen and the Cardiovascular System. Pharmacology and Therapeutics 135:54-70. Invited review. PMID:22484805.
Chen, L, Tingting Liu, Alice Tran, Xiyuan Lu, Alexey A Tomilov, Vanessa Davies, Gino Cortopassi, Donald M. Bers, Marcela Votruba, Anne A. Knowlton. (2012) OPA1 Mutation and Late Onset Cardiomyopathy: Mitochondrial Dysfunction and mtDNA Instability. JAHA 1:doi: 10.1161
Stice, J.P., L. Chen, S.C. Kim, J.S. Jung, A. L. Tran, T. T. Liu and A.A. Knowlton. (2011) 17β-Estradiol, Aging, Inflammation and the Stress Response in the Female Heart. Endocrinology 152:1589-98.
Wang, Y., L. Chen, N. Hagiwara, and A. A. Knowlton.(2010) Regulation of Heat Shock Protein (HSP) 60 and 72 Expression in the Failing Heart. J. Mol. Cell. Cardiol. 48:360-366. PMID: 19945465
Kim, S.C., J.P. Stice, L. Chen, J.S. Jung, Y. Wang, S. Gupta, G. Baumgarten, J. Trial and A. A. Knowlton.(2009) Extracellular Heat Shock Protein 60, Cardiac Myocytes and Apoptosis. Circulation Research 105:1186-1195.
Chen, L., Q. Gong, J.P. Stice, A.A.Knowlton.(2009) Mitochondrial OPA1, Apoptosis and Heart Failure. Cardiovascular Research 84:91-99.PMID:19493956
Stice, J.P., J. Eiserich, and A.A. Knowlton.(2009) Role of Aging vs. Loss of Estrogen in the Reduction in Vascular Function in Female Rats. Endocrinology 150:212-219. PMID: 18787021
Hamilton, K.L., L. Lin, Y. Wang, and A.A.Knowlton.(2008) Effect of Ovariectomy on Cardiac Gene Expression: Inflammation and Changes in SOCS Genes Expression. Physiol. Genomics 32:254-263.PMID: 17986523
Lin, L., S.C. Kim, Y. Wang, S. Gupta, B. Davis, S. I. Simon, G. Torre-Amione, and A.A. Knowlton. (2007) HSP60 in Heart Failure: Abnormal Distribution and Role in Cardiac Myocyte Apoptosis. Am. J. Physiol.293:H2238-47. PMID: 17675567
Gupta, S. & A.A. Knowlton.(2007) HSP60 Trafficking in Adult Cardiac Myocytes: Role of the Exosomal Pathway. Am. J. Physiol. 292:H3052-6. PMID: 17307989
Voss, M.R., S. Gupta, J.P. Stice, G. Baumgarten, Lu, L. J.M. Tristan and A.A.Knowlton. (2005) Effect of Mutation of Amino Acids 246-251 (KRKHKK) in HSP72 on Protein Synthesis and Recovery from Hypoxic Injury. Am. J. Physiol. 289:H2519-H2525. PMID: 16100242
Hamilton, K., Mbai, F.N., S. Gupta and A.A.Knowlton.(2004) Estrogen, Heat Shock Proteins and NFkB in human vascular endothelium. Atherosclerosis and Vascular Biology 24:1628-1633
Voss, M, J. Stallone, M. Li, P. Knuefermann, A.A.Knowlton. (2003) Gender Differences in the Expression of Heat Shock Proteins: The Effect of Estrogen. Am. J. Physiol. 285:H687-H692.
Kirchhoff, S.R., S. Gupta, A.A. Knowlton. (2002) Cytosolic HSP60, apoptosis and myocardial injury. Circulation 105:2899-2904.
Gupta,S. and A.A. Knowlton Cytosolic HSP60, Hypoxia, and Apoptosis. (2002) Circulation 106:2727-2733.