title: Postnatal Loss of Kindlin-2 Leads to Progressive Heart Failure.
abstract: The striated muscle costamere, a multiprotein complex at the boundary between the sarcomere and the sarcolemma, plays an integral role in maintaining striated muscle structure and function. Multiple costamere-associated proteins, such as integrins and integrin-interacting proteins, have been identified and shown to play an increasingly important role in the pathogenesis of human cardiomyopathy. Kindlin-2 is an adaptor protein that binds to the integrin β cytoplasmic tail to promote integrin activation. Genetic deficiency of Kindlin-2 results in embryonic lethality, and knockdown of the Kindlin-2 homolog in Caenorhabditis elegans and Danio rerio suggests that it has an essential role in integrin function and normal muscle structure and function. The precise role of Kindlin-2 in the mammalian cardiac myocyte remains to be determined.
  
  
  
  The current studies were designed to investigate the role of Kindlin-2 in the mammalian heart. We generated a series of cardiac myocyte-specific Kindlin-2 knockout mice with excision of the Kindlin-2 gene in either developing or adult cardiac myocytes. We found that mice lacking Kindlin-2 in the early developing heart are embryonic lethal. We demonstrate that deletion of Kindlin-2 at late gestation or in adult cardiac myocytes resulted in heart failure and premature death, which were associated with enlargement of the heart and extensive fibrosis. In addition, integrin β1D protein expression was significantly downregulated in the adult heart.
  
  
  
  Kindlin-2 is required to maintain integrin β1D protein stability. Postnatal loss of Kindlin-2 from cardiac myocytes leads to progressive heart failure, showing the importance of costameric proteins like Kindlin-2 for homeostasis of normal heart function.
authors: From the Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.Z., X.Z.); Department of Medicine-Cardiology, University of California San Diego, La Jolla (Z.Z., Y.M., J.V., A.K.P., A.M.M., W.H.B., N.D.D., K.L.P., K.U.K., R.S.R., J.C.); Veterans Administration Healthcare, Medicine/Cardiology, San Diego, CA (A.M.M., R.S.R.).
authors: Zhiyuan
authors: Z
authors: Zhang
authors: From the Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.Z., X.Z.); Department of Medicine-Cardiology, University of California San Diego, La Jolla (Z.Z., Y.M., J.V., A.K.P., A.M.M., W.H.B., N.D.D., K.L.P., K.U.K., R.S.R., J.C.); Veterans Administration Healthcare, Medicine/Cardiology, San Diego, CA (A.M.M., R.S.R.).
authors: Yongxin
authors: Y
authors: Mu
authors: From the Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.Z., X.Z.); Department of Medicine-Cardiology, University of California San Diego, La Jolla (Z.Z., Y.M., J.V., A.K.P., A.M.M., W.H.B., N.D.D., K.L.P., K.U.K., R.S.R., J.C.); Veterans Administration Healthcare, Medicine/Cardiology, San Diego, CA (A.M.M., R.S.R.).
authors: Jennifer
authors: J
authors: Veevers
authors: From the Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.Z., X.Z.); Department of Medicine-Cardiology, University of California San Diego, La Jolla (Z.Z., Y.M., J.V., A.K.P., A.M.M., W.H.B., N.D.D., K.L.P., K.U.K., R.S.R., J.C.); Veterans Administration Healthcare, Medicine/Cardiology, San Diego, CA (A.M.M., R.S.R.).
authors: Angela K
authors: AK
authors: Peter
authors: From the Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.Z., X.Z.); Department of Medicine-Cardiology, University of California San Diego, La Jolla (Z.Z., Y.M., J.V., A.K.P., A.M.M., W.H.B., N.D.D., K.L.P., K.U.K., R.S.R., J.C.); Veterans Administration Healthcare, Medicine/Cardiology, San Diego, CA (A.M.M., R.S.R.).
authors: Ana Maria
authors: AM
authors: Manso
authors: From the Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.Z., X.Z.); Department of Medicine-Cardiology, University of California San Diego, La Jolla (Z.Z., Y.M., J.V., A.K.P., A.M.M., W.H.B., N.D.D., K.L.P., K.U.K., R.S.R., J.C.); Veterans Administration Healthcare, Medicine/Cardiology, San Diego, CA (A.M.M., R.S.R.).
authors: William H
authors: WH
authors: Bradford
authors: From the Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.Z., X.Z.); Department of Medicine-Cardiology, University of California San Diego, La Jolla (Z.Z., Y.M., J.V., A.K.P., A.M.M., W.H.B., N.D.D., K.L.P., K.U.K., R.S.R., J.C.); Veterans Administration Healthcare, Medicine/Cardiology, San Diego, CA (A.M.M., R.S.R.).
authors: Nancy D
authors: ND
authors: Dalton
authors: From the Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.Z., X.Z.); Department of Medicine-Cardiology, University of California San Diego, La Jolla (Z.Z., Y.M., J.V., A.K.P., A.M.M., W.H.B., N.D.D., K.L.P., K.U.K., R.S.R., J.C.); Veterans Administration Healthcare, Medicine/Cardiology, San Diego, CA (A.M.M., R.S.R.).
authors: Kirk L
authors: KL
authors: Peterson
authors: From the Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.Z., X.Z.); Department of Medicine-Cardiology, University of California San Diego, La Jolla (Z.Z., Y.M., J.V., A.K.P., A.M.M., W.H.B., N.D.D., K.L.P., K.U.K., R.S.R., J.C.); Veterans Administration Healthcare, Medicine/Cardiology, San Diego, CA (A.M.M., R.S.R.).
authors: Kirk U
authors: KU
authors: Knowlton
authors: From the Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.Z., X.Z.); Department of Medicine-Cardiology, University of California San Diego, La Jolla (Z.Z., Y.M., J.V., A.K.P., A.M.M., W.H.B., N.D.D., K.L.P., K.U.K., R.S.R., J.C.); Veterans Administration Healthcare, Medicine/Cardiology, San Diego, CA (A.M.M., R.S.R.).
authors: Robert S
authors: RS
authors: Ross
authors: From the Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.Z., X.Z.); Department of Medicine-Cardiology, University of California San Diego, La Jolla (Z.Z., Y.M., J.V., A.K.P., A.M.M., W.H.B., N.D.D., K.L.P., K.U.K., R.S.R., J.C.); Veterans Administration Healthcare, Medicine/Cardiology, San Diego, CA (A.M.M., R.S.R.).
authors: Xinmin
authors: X
authors: Zhou
authors: From the Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China (Z.Z., X.Z.); Department of Medicine-Cardiology, University of California San Diego, La Jolla (Z.Z., Y.M., J.V., A.K.P., A.M.M., W.H.B., N.D.D., K.L.P., K.U.K., R.S.R., J.C.); Veterans Administration Healthcare, Medicine/Cardiology, San Diego, CA (A.M.M., R.S.R.). juchen@ucsd.edu.
authors: Ju
authors: J
authors: Chen
mesh_terms: D000367:Age Factors; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000235:genetics; D018450:Disease Progression; D015536:Down-Regulation; D005355:Fibrosis; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D005865:Gestational Age; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype
chemical_list: D003598:Cytoskeletal Proteins; D019012:Integrin beta1; D009124:Muscle Proteins; C527802:kindlin-2 protein, mouse
keywords: cardiomyopathies; integrins; mice, knockout; myocytes, cardiac; sarcolemma