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Ann Thorac Surg 2007;83:946-953
© 2007 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Transforming Growth Factor-ß1 Mechanisms in Aortic Valve Calcification: Increased Alkaline Phosphatase and Related Events

^a Division of Cardiology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
^b University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Accepted for publication October 6, 2006.

^_* Address correspondence to Dr Levy, Children’s Hospital of Philadelphia, Abramson Research Center, Suite 702, 3615 Civic Center Boulevard, Philadelphia, PA 19104-4318 (Email: levyr{at}email.chop.edu).

Background: Aortic valve stenosis is the most frequent indication for valve replacement surgery, and is commonly associated with pathologic calcification. Previous investigations by our group have shown a strong association of transforming growth factor-beta1 (TGF-ß1)-related mechanisms with calcific aortic stenosis in both cell culture and clinical pathology studies.

Methods: In the present investigations we sought to investigate the sequence of events involved in TGF-ß1-initiated aortic valve interstitial cell calcification in cell culture, and to study related gene expression pattern differences comparing calcific aortic stenosis surgical specimens with normal aortic valve leaflets.

Results: Sheep aortic valve interstitial cells (SAVIC) in culture progressively calcified over 14 days after the addition of TGF-ß1 to a significantly greater extent than non-TGF-ß1 controls. The TGF-ß1-induced SAVIC calcification was associated with maximal levels of alkaline phosphatase by 72 hours. Annexin V positive apoptosis was increased in TGF-ß1-treated SAVIC cultures at 14 days compared with controls. Matrix metalloproteinase 9 per gel zymography was detectable only in SAVIC cultures treated with TGF-ß1 from seven days on. Matrix metalloproteinase 2 was present in all SAVIC cultures per gel zymograms, either with or without TGF-ß1, but the active form of matrix metalloproteinase 2 significantly increased over 14 days in response to TGF-ß1. Quantitative gene expression studies (re: RNA levels) of human aortic valve cusps obtained at cardiac surgery demonstrated a number of related trends, including upregulation of the expression of TGF-ß1, alkaline phosphatase, and matrix metalloproteinase 9 in calcified human aortic valves.

Conclusions: Transforming growth factor-ß1 causes SAVIC to calcify due to an early maximal increase in alkaline phosphatase activity with associated apoptotic events and increased matrix metalloproteinase 9. These TGF-ß1-related mechanistic events may be of clinical relevance based upon the gene expression pattern changes observed in calcific aortic stenosis valve cusps.

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