Repair and replacement of the leaky mitral valve are common cardiac surgical operations that are most frequently necessitated by myxomatous degeneration of the mitral valve. This degenerative condition can additionally exhibit severe cardiovascular complications including heart arrhythmias, sudden death, stroke and heart failure in the elderly. Genetic analyses show that myxomatous degeneration can arise from defects in one of several genes; however, the major causative genes have yet to be identified. Inheritance of just a single gene is insufficient to predict the development of clinical disease. Thus, severe disease likely results from an interaction between multiple genes, ageing and physiology. At present, there is no animal system to evaluate such complex interactions. We have generated mice deficient for the Hs3stl gene (Hs3st1-/-) and its encoded enzyme, 3OST1. Aged Hs3st1-/- mice develop myxomatous degeneration in at least mitral and aortic valves. This animal provides a unique opportunity to evaluate how aging, genetic and physiologic factors interact and contribute to the development of myxomatous degenerative valve disease and it' deleterious cardiovascular sequelae. We propose to: (1) Establish the influence of aging, gender and 3OST1 deficiency on the myxomatous degeneration of individual heart valves and assess the cardiovascular consequences of heart valve dysfunction. This will be accomplished by evaluating Hs3stl +and wild-type littermate controls (Hs3st1 +/+) at defined age points for alterations in valve and cardiac structure and function. (2) Evaluate the interplay between aging, hypertension and 3OST1 deficiency on myxomatous valvular degeneration of heart valves. Surgical constriction of the aorta will be conducted on Hs3st1+ and Hs3stl +/+ mice to induce moderate hypertension. At defined age points, each heart valve and the heart will be examined for alterations in structure and function. (3) Test for involvement of 3OST1 in human myxomatous mitral valve prolapse. A pilot case control study will examine whether 3OST1 plasma levels are associated with this disease in general or with specific patient subcategories. Archival human valve tissues will also be examined to test for local tissue reductions in 3OST1 product. (4) Distinguish whether the protective effects of 3OST1 stem from its action within endothelial cells or from a systemic influences of plasma borne enzyme. Transgenic mice shall be generated to express secreted or nonsecreted forms of 3OST1+ selectively in vascular endothelial cells. Selective correction of disease in Hs3st1+ mice will reveal the critical site of action. Together these studies provide the foundations for elucidating the molecular basis of this valvular disease and will provide a rigorously characterized model for elucidating how severe myxomatous disease results from interactions between multiple causative genes, aging and physiology.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG023590-04
Application #
7364631
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Kohanski, Ronald A
Project Start
2005-02-15
Project End
2010-01-31
Budget Start
2008-03-01
Budget End
2010-01-31
Support Year
4
Fiscal Year
2008
Total Cost
$237,731
Indirect Cost
Name
Dartmouth College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Smits, Nicole C; Kobayashi, Takashi; Srivastava, Pratyaksh K et al. (2017) HS3ST1 genotype regulates antithrombin's inflammomodulatory tone and associates with atherosclerosis. Matrix Biol 63:69-90
Kerley-Hamilton, Joanna S; Trask, Heidi W; Ridley, Christian J A et al. (2012) Obesity is mediated by differential aryl hydrocarbon receptor signaling in mice fed a Western diet. Environ Health Perspect 120:1252-9
Fung, Erik; Patsopoulos, Nikolaos A; Belknap, Steven M et al. (2012) Effect of genetic variants, especially CYP2C9 and VKORC1, on the pharmacology of warfarin. Semin Thromb Hemost 38:893-904
Kerley-Hamilton, Joanna S; Trask, Heidi W; Ridley, Christian J A et al. (2012) Inherent and benzo[a]pyrene-induced differential aryl hydrocarbon receptor signaling greatly affects life span, atherosclerosis, cardiac gene expression, and body and heart growth in mice. Toxicol Sci 126:391-404
Shworak, Nicholas W; Kobayashi, Takashi; de Agostini, Ariane et al. (2010) Anticoagulant heparan sulfate to not clot--or not? Prog Mol Biol Transl Sci 93:153-78
Smits, Nicole C; Shworak, Nicholas W; Dekhuijzen, P N Richard et al. (2010) Heparan sulfates in the lung: structure, diversity, and role in pulmonary emphysema. Anat Rec (Hoboken) 293:955-67
Lawrence, Roger; Yabe, Tomio; Hajmohammadi, Sassan et al. (2007) The principal neuronal gD-type 3-O-sulfotransferases and their products in central and peripheral nervous system tissues. Matrix Biol 26:442-55