EXPEDITED REVIEW
Human Degenerative Valve Disease Is Associated With Up-Regulation of Low-Density Lipoprotein Receptor-Related Protein 5 Receptor-Mediated Bone Formation
Frank C. Caira, BSc*,
Stuart R. Stock, PhD ,
Thomas G. Gleason, MD*,
Edwin C. McGee, MD*,
Jie Huang, ScD ,
Robert O. Bonow, MD, FACC*,
Thomas C. Spelsberg, PhD ,
Patrick M. McCarthy, MD, FACC*,
Shahbudin H. Rahimtoola, MB, FRCP, DSc, MACC, MACP|| and
Nalini M. Rajamannan, MD, FACC*,a,*
* Division of Cardiology and Cardiothoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
Institute for Bioengineering and Nanoscience in Advanced Medicine, Northwestern University, Chicago, Illinois
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
Department of Molecular Biology and Biochemistry, Mayo Clinic College of Medicine, Rochester, Minnesota
|| Division of Cardiovascular Medicine, Department of Medicine, LAC + USC Medical Center, Keck School of Medicine at the University of Southern California, Los Angeles, California
Manuscript received January 6, 2006;
revised manuscript received February 9, 2006,
accepted February 14, 2006.
* Reprint requests and correspondence: Dr. Nalini M. Rajamannan, Northwestern University Feinberg School of Medicine, 300 East Chicago Avenue, Tarry 12-717, Chicago, Illinois 60611. (Email: n-rajamannan{at}northwestern.edu).
OBJECTIVES: The goal of this research was to define the cellular mechanisms involved in myxomatous mitral valve disease and calcific aortic valve disease and to redefine the term degenerative valve disease in terms of an active cellular biology.
BACKGROUND: "Degenerative" valvular heart disease is the primary cause of regurgitant and stenotic valvular lesion in the U.S. However, the signaling pathways are not known. We hypothesize that valve degeneration occurs due to an osteoblastic differentiation process mediated by the low-density lipoprotein receptor-related protein 5 (Lrp5) signaling pathway to cause valve thickening.
METHODS: We examined human diseased valves: myxomatous mitral valves (n = 23), calcified tricuspid aortic valves (n = 27), calcified bicuspid aortic valves (n = 23), and control tissue from mitral and aortic valves (n = 40). The valves were examined by reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry for signaling markers important in osteoblast differentiation: Sox9 and Cbfa1 (transcription factors for osteoblast differentiation); Lrp5 and Wnt3 (osteoblast differentiation signaling marker), osteopontin and osteocalcin (osteoblast endochrondral bone matrix proteins), and proliferating cell nuclear antigen (a marker of cell proliferation). Cartilage development and bone formation was measured by Alcian blue stain and Alizarin red stain. Computed Scano MicroCT-40 (Bassersdorf, Switzerland) analysis measured calcium burden.
RESULTS: Low-density lipoprotein receptor-related protein 5, osteocalcin, and other osteochrondrogenic differentiation markers were increased in the calcified aortic valves by protein and gene expression (p > 0.001). Sox9, Lrp5 receptor, and osteocalcin were increased in myxomatous mitral valves by protein and gene expression (p > 0.001). MicroCT was positive in the calcified aortic valves and negative in the myxomatous mitral valves.
CONCLUSIONS: The mechanism of valvular heart disease involves an endochondral bone process that is expressed as cartilage in the mitral valves and bone in the aortic valves. Up-regulation of the Lrp5 pathway may play a role in the mechanism for valvular heart disease.
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Abbreviations and Acronyms
| | Lrp5 = low-density lipoprotein receptor-related protein 5 | | PCNA = proliferating cell nuclear antigen | | RNA = ribonucleic acid | | RT-PCR = reverse transcriptase-polymerase chain reaction |
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