Cadherin-11 Overexpression Induces Extracellular Matrix Remodeling and Calcification in Mature Aortic Valves.
Calcific aortic valve (AoV) disease is a significant clinical problem for which the regulatory mechanisms are poorly understood. Enhanced cell-cell adhesion is a common mechanism of cellular aggregation, but its role in calcific lesion formation is not known. Cadherin-11 (Cad-11) has been associated with lesion formation in vitro, but its function during adult valve homeostasis and pathogenesis is not known. This study aims to elucidate the specific functions of Cad-11 and its downstream targets, RhoA and Sox9, in extracellular matrix remodeling and AoV calcification.



We conditionally overexpressed Cad-11 in murine heart valves using a novel double-transgenic Nfatc1(Cre);R26-Cad11(TglTg) mouse model. These mice developed hemodynamically significant aortic stenosis with prominent calcific lesions in the AoV leaflets. Cad-11 overexpression upregulated downstream targets, RhoA and Sox9, in the valve interstitial cells, causing calcification and extensive pathogenic extracellular matrix remodeling. AoV interstitial cells overexpressing Cad-11 in an osteogenic environment in vitro rapidly form calcific nodules analogous to in vivo lesions. Molecular analyses revealed upregulation of osteoblastic and myofibroblastic markers. Treatment with a Rho-associated protein kinase inhibitor attenuated nodule formation, further supporting that Cad-11-driven calcification acts through the small GTPase RhoA/Rho-associated protein kinase signaling pathway.



This study identifies one of the underlying molecular mechanisms of heart valve calcification and demonstrates that overexpression of Cad-11 upregulates RhoA and Sox9 to induce calcification and extracellular matrix remodeling in adult AoV pathogenesis. The findings provide a potential molecular target for clinical treatment.
From the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Derek C
DC
Sung
From the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Caitlin J
CJ
Bowen
From the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Kiran A
KA
Vaidya
From the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Jingjing
J
Zhou
From the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Nikita
N
Chapurin
From the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Andrew
A
Recknagel
From the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Bin
B
Zhou
From the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Jonathan
J
Chen
From the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.).
Michael
M
Kotlikoff
From the Meinig School of Biomedical Engineering (D.C.S., C.J.B., K.A.V., J.Z., N.C., A.R., J.T.B.) and Department of Biomedical Sciences (M.K.), Cornell University, Ithaca, NY; Department of Genetics, Pediatrics, and Medicine (Cardiology), Albert Einstein College of Medicine, Montefiore Medical Center, New York (B.Z.); and Department of Pediatric Cardiovascular Surgery, Seattle Children's Hospital, WA (J.C.). jtb47@cornell.edu.
Jonathan T
JT
Butcher
D000818:Animals; D001021:Aortic Valve / Q000378:metabolism* / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D055758:SOX9 Transcription Factor / Q000378:metabolism; D012720:Severity of Illness Index; D022502:Stress Fibers / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D015820:Cadherins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse; C066737:RHOA protein, human; C086960:osteoblast cadherin; D054460:rho-Associated Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
aortic valve; cadherin; cell adhesion; extracellular matrix; stenosis