Christopher Kontos

Overview:

The Kontos Lab studies the molecular mechanisms of angiogenesis and vascular remodeling. Studies are directed toward understanding how signal transduction by endothelial receptor tyrosine kinase (RTKs) regulates vascular growth in both physiological and pathological processes, including exercise, peripheral artery disease (PAD), atherosclerosis, and cancer.

Current projects include:

1. Signal transduction, mechanisms of activation, and downregulation of endothelial RTKs (mainly Tie1, Tie2, VEGFR-1, and VEGFR-2)

2. Differential effects of the Angiopoietins

3. Role of the inositol phosphatase PTEN in the regulation of vascular cell growth and remodeling

4. PTEN gene therapy for prevention of vein graft disease

5. Angiogenic signaling in skeletal muscle, including mechanisms of exercise-induced angiogenesis

6. Proteolytic cleavage and shedding of endothelial RTKs

7. Angiogenic proteins as biomarkers in peripheral artery disease

Positions:

Professor of Medicine

Medicine, Cardiology
School of Medicine

Director, Medical Scientist Training Program

Medicine, Cardiology
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1989

Virginia Commonwealth University

Fellow in Cardiology, Medicine

Duke University

Grants:

A fully biological platform for monitoring mesoscale neural activity

Administered By
Psychiatry & Behavioral Sciences, Brain Stimulation and Neurophysiology
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

TIE2 Activation for the Treatment of Chemical-Induced Acute Lung Injury

Administered By
Medicine, Cardiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Tie2 Activation for the Treatment of Chemical-Induced Acute Lung Injury

Administered By
Medicine, Cardiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

The Role of PTEN in Endothelial Biology

Administered By
Medicine, Cardiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Endothelial Cell Molecular Alterations in Cancer

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Publications:

A systems biology model of junctional localization and downstream signaling of the Ang-Tie signaling pathway.

The Ang-Tie signaling pathway is an important vascular signaling pathway regulating vascular growth and stability. Dysregulation in the pathway is associated with vascular dysfunction and numerous diseases that involve abnormal vascular permeability and endothelial cell inflammation. The understanding of the molecular mechanisms of the Ang-Tie pathway has been limited due to the complex reaction network formed by the ligands, receptors, and molecular regulatory mechanisms. In this study, we developed a mechanistic computational model of the Ang-Tie signaling pathway validated against experimental data. The model captures and reproduces the experimentally observed junctional localization and downstream signaling of the Ang-Tie signaling axis, as well as the time-dependent role of receptor Tie1. The model predicts that Tie1 modulates Tie2's response to the context-dependent agonist Ang2 by junctional interactions. Furthermore, modulation of Tie1's junctional localization, inhibition of Tie2 extracellular domain cleavage, and inhibition of VE-PTP are identified as potential molecular strategies for potentiating Ang2's agonistic activity and rescuing Tie2 signaling in inflammatory endothelial cells.
Authors
Zhang, Y; Kontos, CD; Annex, BH; Popel, AS
MLA Citation
Zhang, Yu, et al. “A systems biology model of junctional localization and downstream signaling of the Ang-Tie signaling pathway.Npj Syst Biol Appl, vol. 7, no. 1, Aug. 2021, p. 34. Pubmed, doi:10.1038/s41540-021-00194-6.
URI
https://scholars.duke.edu/individual/pub1494294
PMID
34417472
Source
pubmed
Published In
Npj Syst Biol Appl
Volume
7
Published Date
Start Page
34
DOI
10.1038/s41540-021-00194-6

Mitochondrial dysfunction in human immunodeficiency virus-1 transgenic mouse cardiac myocytes.

The pathophysiology of human immunodeficiency virus (HIV)-associated cardiomyopathy remains uncertain. We used HIV-1 transgenic (Tg26) mice to explore mechanisms by which HIV-related proteins impacted on myocyte function. Compared to adult ventricular myocytes isolated from nontransgenic (wild type [WT]) littermates, Tg26 myocytes had similar mitochondrial membrane potential (ΔΨ m ) under normoxic conditions but lower Δ Ψ m after hypoxia/reoxygenation (H/R). In addition, Δ Ψ m in Tg26 myocytes failed to recover after Ca 2+ challenge. Functionally, mitochondrial Ca 2+ uptake was severely impaired in Tg26 myocytes. Basal and maximal oxygen consumption rates (OCR) were lower in normoxic Tg26 myocytes, and further reduced after H/R. Complex I subunit and ATP levels were lower in Tg26 hearts. Post-H/R, mitochondrial superoxide (O 2 •- ) levels were higher in Tg26 compared to WT myocytes. Overexpression of B-cell lymphoma 2-associated athanogene 3 (BAG3) reduced O 2 •- levels in hypoxic WT and Tg26 myocytes back to normal. Under normoxic conditions, single myocyte contraction dynamics were similar between WT and Tg26 myocytes. Post-H/R and in the presence of isoproterenol, myocyte contraction amplitudes were lower in Tg26 myocytes. BAG3 overexpression restored Tg26 myocyte contraction amplitudes to those measured in WT myocytes post-H/R. Coimmunoprecipitation experiments demonstrated physical association of BAG3 and the HIV protein Tat. We conclude: (a) Under basal conditions, mitochondrial Ca 2+ uptake, OCR, and ATP levels were lower in Tg26 myocytes; (b) post-H/R, Δ Ψ m was lower, mitochondrial O 2 •- levels were higher, and contraction amplitudes were reduced in Tg26 myocytes; and (c) BAG3 overexpression decreased O 2 •- levels and restored contraction amplitudes to normal in Tg26 myocytes post-H/R in the presence of isoproterenol.
Authors
Cheung, JY; Gordon, J; Wang, J; Song, J; Zhang, X-Q; Prado, FJ; Shanmughapriya, S; Rajan, S; Tomar, D; Tahrir, FG; Gupta, MK; Knezevic, T; Merabova, N; Kontos, CD; McClung, JM; Klotman, PE; Madesh, M; Khalili, K; Feldman, AM
MLA Citation
Cheung, Joseph Y., et al. “Mitochondrial dysfunction in human immunodeficiency virus-1 transgenic mouse cardiac myocytes.J Cell Physiol, vol. 234, no. 4, Apr. 2019, pp. 4432–44. Pubmed, doi:10.1002/jcp.27232.
URI
https://scholars.duke.edu/individual/pub1350077
PMID
30256393
Source
pubmed
Published In
J Cell Physiol
Volume
234
Published Date
Start Page
4432
End Page
4444
DOI
10.1002/jcp.27232

Association of Variants in BAG3 With Cardiomyopathy Outcomes in African American Individuals.

Importance: The prevalence of nonischemic dilated cardiomyopathy (DCM) is greater in individuals of African ancestry than in individuals of European ancestry. However, little is known about whether the difference in prevalence or outcomes is associated with functional genetic variants. Objective: We hypothesized that Bcl2-associated anthanogene 3 (BAG3) genetic variants were associated with outcomes in individuals of African ancestry with DCM. Design: This multicohort study of the BAG3 genotype in patients of African ancestry with dilated cardiomyopathy uses DNA obtained from African American individuals enrolled in 3 clinical studies: the Genetic Risk Assessment of African Americans With Heart Failure (GRAHF) study; the Intervention in Myocarditis and Acute Cardiomyopathy Trial-2 (IMAC-2) study; and the Genetic Risk Assessment of Cardiac Events (GRACE) study. Samples of DNA were also acquired from the left ventricular myocardium of patients of African ancestry who underwent heart transplant at the University of Colorado and University of Pittsburgh. Main Outcomes and Measures: The primary end points were the prevalence of BAG3 mutations in African American individuals and event-free survival in participants harboring functional BAG3 mutations. Results: Four BAG3 genetic variants were identified; these were expressed in 42 of 402 African American individuals (10.4%) with nonischemic heart failure and 9 of 107 African American individuals (8.4%) with ischemic heart failure but were not present in a reference population of European ancestry (P < .001). The variants included 2 nonsynonymous single-nucleotide variants; 1 three-nucleotide in-frame insertion; and 2 single-nucleotide variants that were linked in cis. The presence of BAG3 variants was associated with a nearly 2-fold (hazard ratio, 1.97 [95% CI, 1.19-3.24]; P = .01) increase in cardiac events in carriers compared with noncarriers. Transfection of transformed adult human ventricular myocytes with plasmids expressing the 4 variants demonstrated that each variant caused an increase in apoptosis and a decrease in autophagy when samples were subjected to the stress of hypoxia-reoxygenation. Conclusions and Relevance: This study demonstrates that genetic variants in BAG3 found almost exclusively in individuals of African ancestry were not causative of disease but were associated with a negative outcome in patients with a dilated cardiomyopathy through modulation of the function of BAG3. The results emphasize the importance of biological differences in causing phenotypic variance across diverse patient populations, the need to include diverse populations in genetic cohorts, and the importance of determining the pathogenicity of genetic variants.
Authors
Myers, VD; Gerhard, GS; McNamara, DM; Tomar, D; Madesh, M; Kaniper, S; Ramsey, FV; Fisher, SG; Ingersoll, RG; Kasch-Semenza, L; Wang, J; Hanley-Yanez, K; Lemster, B; Schwisow, JA; Ambardekar, AV; Degann, SH; Bristow, MR; Sheppard, R; Alexis, JD; Tilley, DG; Kontos, CD; McClung, JM; Taylor, AL; Yancy, CW; Khalili, K; Seidman, JG; Seidman, CE; McTiernan, CF; Cheung, JY; Feldman, AM
MLA Citation
Myers, Valerie D., et al. “Association of Variants in BAG3 With Cardiomyopathy Outcomes in African American Individuals.Jama Cardiol, vol. 3, no. 10, Oct. 2018, pp. 929–38. Pubmed, doi:10.1001/jamacardio.2018.2541.
URI
https://scholars.duke.edu/individual/pub1344258
PMID
30140897
Source
pubmed
Published In
Jama Cardiol
Volume
3
Published Date
Start Page
929
End Page
938
DOI
10.1001/jamacardio.2018.2541

Addressing the physician-scientist pipeline: strategies to integrate research into clinical training programs.

Authors
Permar, SR; Ward, RA; Barrett, KJ; Freel, SA; Gbadegesin, RA; Kontos, CD; Hu, PJ; Hartmann, KE; Williams, CS; Vyas, JM
MLA Citation
Permar, Sallie R., et al. “Addressing the physician-scientist pipeline: strategies to integrate research into clinical training programs.J Clin Invest, vol. 130, no. 3, Mar. 2020, pp. 1058–61. Pubmed, doi:10.1172/JCI136181.
URI
https://scholars.duke.edu/individual/pub1431948
PMID
32039914
Source
pubmed
Published In
J Clin Invest
Volume
130
Published Date
Start Page
1058
End Page
1061
DOI
10.1172/JCI136181

Angiopoietin-Tie Signaling Pathway in Endothelial Cells: A Computational Model.

The angiopoietin-Tie signaling pathway is an important vascular signaling pathway involved in angiogenesis, vascular stability, and quiescence. Dysregulation in the pathway is linked to the impairments in vascular function associated with many diseases, including cancer, ocular diseases, systemic inflammation, and cardiovascular diseases. The present study uses a computational signaling pathway model validated against experimental data to quantitatively study various mechanistic aspects of the angiopoietin-Tie signaling pathway, including receptor activation, trafficking, turnover, and molecular mechanisms of its regulation. The model provides mechanistic insights into the controversial role of Ang2 and its regulators vascular endothelial protein tyrosine phosphatase (VE-PTP) and Tie1 and predicts synergistic effects of inhibition of VE-PTP, Tie1, and Tie2 cleavage on enhancing the vascular protective actions of Tie2.
Authors
Zhang, Y; Kontos, CD; Annex, BH; Popel, AS
MLA Citation
Zhang, Yu, et al. “Angiopoietin-Tie Signaling Pathway in Endothelial Cells: A Computational Model.Iscience, vol. 20, Oct. 2019, pp. 497–511. Pubmed, doi:10.1016/j.isci.2019.10.006.
URI
https://scholars.duke.edu/individual/pub1407767
PMID
31655061
Source
pubmed
Published In
Iscience
Volume
20
Published Date
Start Page
497
End Page
511
DOI
10.1016/j.isci.2019.10.006