Abstract
Kindlin-2, a member of the Kindlin family focal adhesion proteins, plays an important role in cardiac development. It is known that defects in the Z-disc proteins lead to hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). Our previous investigation showed that Kindlin-2 is mainly localized at the Z-disc and depletion of Kindlin-2 disrupts the structure of the Z-Disc. Here, we reported that depletion of Kindlin-2 leads to the disordered myocardial fibers, fractured and vacuolar degeneration in myocardial fibers. Interestingly, depletion of Kindlin-2 in mice induced cardiac myocyte hypertrophy and increased the heart weight. Furthermore, decreased expression of Kindlin-2 led to cardiac dysfunction and also markedly impairs systolic function. Our data indicated that Kindlin-2 not only maintains the cardiac structure but also is required for cardiac function.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Ahmad, F., Seidman, J.G., and Seidman, C.E. (2005). The genetic basis for cardiac remodeling. Annu Rev Genomics Hum Genet 6, 185–216.
Arad, M., Seidman, J.G., and Seidman, C.E. (2002). Phenotypic diversity in hypertrophic cardiomyopathy. Hum Mol Genet 11, 2499–2506.
Bagnall, R.D., Molloy, L.K., Kalman, J.M., and Semsarian, C. (2014). Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death. BMC Med Genet 15, 99.
Dowling, J.J., Gibbs, E., Russell, M., Goldman, D., Minarcik, J., Golden, J.A., and Feldman, E.L. (2008). Kindlin-2 is an essential component of intercalated discs and is required for vertebrate cardiac structure and function. Circ Res 102, 423–431.
Ervasti, J.M. (2003). Costameres: the Achilles’ heel of Herculean muscle. J Bio Chem 278, 13591–13594.
Frank, D., Kuhn, C., Katus, H.A., and Frey, N. (2006). The sarcomeric Z-disc: a nodal point in signalling and disease. J Mol Med 84, 446–468.
Frank, D., Kuhn, C., Katus, H.A., and Frey, N. (2007). Role of the sarcomeric Z-disc in the pathogenesis of cardiomyopathy. Future Cardiol 3, 611–622.
Grunig, E., Tasman, J.A., Kucherer, H., Franz, W., Kubler, W., and Katus, H.A. (1998). Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol 31, 186–194.
Huang, Y., Xia, J., Zheng, J., Geng, B., Liu, P., Yu, F., Liu, B., Zhang, H., Xu, M., Ye, P., Zhu, Y., Xu, Q., Wang, X., and Kong, W. (2013). Deficiency of cartilage oligomeric matrix protein causes dilated cardiomyopathy. Basic Res Cardiol 108, 374.
Ma, Y.Q., Qin, J., Wu, C., and Plow, E.F. (2008). Kindlin-2 (Mig-2): a co-activator of beta3 integrins. J Cell Biol 181, 439–446.
Marian, A.J., and Roberts, R. (2001). The molecular genetic basis for hypertrophic cardiomyopathy. J Mol Cell Cardiol 33, 655–670.
Marsiglia, J.D., and Pereira, A.C. (2014). Hypertrophic cardiomyopathy: how do mutations lead to disease? Arq Bras Cardiol 102, 295–304.
Meves, A., Stremmel, C., Gottschalk, K., and Fassler, R. (2009). The Kindlin protein family: new members to the club of focal adhesion proteins. Trends Cell Biol 19, 504–513.
Mu, W., Zhang, Q., Tang, X., Fu, W., Zheng, W., Lu, Y., Li, H., Wei, Y., Li, L., She, Z., Chen, H., and Liu, D. (2014). Overexpression of a dominant-negative mutant of SIRT1 in mouse heart causes cardiomyocyte apoptosis and early-onset heart failure. Sci China Life Sci 57, 915–924.
Pluskota, E., Dowling, J.J., Gordon, N., Golden, J.A., Szpak, D., West, X.Z., Nestor, C., Ma, Y.Q., Bialkowska, K., Byzova, T., and Plow, E.F. (2011). The integrin coactivator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish. Blood 117, 4978–4987.
Pluskota, E., Ma, Y., Bledzka, K.M., Bialkowska, K., Soloviev, D.A., Szpak, D., Podrez, E.A., Fox, P.L., Hazen, S.L., Dowling, J.J., Ma, Y.Q., and Plow, E.F. (2013). Kindlin-2 regulates hemostasis by controlling endothelial cell-surface expression of ADP/AMP catabolic enzymes via a clathrin-dependent mechanism. Blood 122, 2491–2499.
Qi, L., Yu, Y., Chi, X., Xu, W., Lu, D., Song, Y., Zhang, Y., and Zhang, H. (2015). Kindlin-2 interacts with alpha-actinin-2 and beta1 integrin to maintain the integrity of the Z-disc in cardiac muscles. FEBS Lett 589, 2155–2162.
Traister, A., Walsh, M., Aafaqi, S., Lu, M., Dai, X., Henkleman, M.R., Momen, A., Zhou, Y.Q., Husain, M., Arab, S., Piran, S., Hannigan, G., and Coles, J.G. (2013). Mutation in integrin-linked kinase (ILK(R211A)) and heat-shock protein 70 comprise a broadly cardioprotective complex. PLoS One 8, e77331.
Vatta, M., Mohapatra, B., Jimenez, S., Sanchez, X., Faulkner, G., Perles, Z., Sinagra, G., Lin, J.H., Vu, T.M., Zhou, Q., Bowles, K.R., Di Lenarda, A., Schimmenti, L., Fox, M., Chrisco, M.A., Murphy, R.T., McKenna, W., Elliott, P., Bowles, N.E., Chen, J., Valle, G., and Towbin, J.A. (2003). Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction. J Am Coll Cardiol 42, 2014–2027.
Wang, H., Li, Z., Wang, J., Sun, K., Cui, Q., Song, L., Zou, Y., Wang, X., Liu, X., Hui, R., and Fan, Y. (2010). Mutations in NEXN, a Z-disc gene, are associated with hypertrophic cardiomyopathy. Am J Hum Genet 87, 687–693.
Wang, Y., Ma, S., Wang, Q., Hu, W., Wang, D., Li, X., Su, T., Qin, X., Zhang, X., Ma, K., Chen, J., Xiong, L., and Cao, F. (2014). Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart. Sci China Life Sci 57, 201–208.
Wei, X., Xia, Y., Li, F., Tang, Y., Nie, J., Liu, Y., Zhou, Z., Zhang, H., and Hou, F.F. (2013). Kindlin-2 mediates activation of TGF-beta/Smad signaling and renal fibrosis. J Am Soc Nephrol 24, 1387–1398.
Wu, C., Jiao, H., Lai, Y., Zheng, W., Chen, K., Qu, H., Deng, W., Song, P., Zhu, K., Cao, H., Galson, D.L., Fan, J., Im, H.J., Liu, Y., Chen, J., Chen, D., and Xiao, G. (2015). Kindlin-2 controls TGF-beta signalling and Sox9 expression to regulate chondrogenesis. Nat Commun 6, 7531.
Yang, J.C., and Xu, X.L. (2012). alpha-Actinin2 is required for the lateral alignment of Z discs and ventricular chamber enlargement during zebrafish cardiogenesis. FASEB J 26, 4230–4242.
Yu, Y., Qi, L., Wu, J., Wang, Y., Fang, W., and Zhang, H. (2013). Kindlin 2 regulates myogenic related factor myogenin via a canonical Wnt signaling in myogenic differentiation. PLoS One 8, e63490.
Zhan, J., Yang, M., Chi, X., Zhang, J., Pei, X., Ren, C., Guo, Y., Liu, W., and Zhang, H. (2014). Kindlin-2 expression in adult tissues correlates with their embryonic origins. Sci China Life Sci 57, 690–697.
Zhan, J., Yang, M., Zhang, J., Guo, Y., Liu, W., and Zhang, H. (2015). Kindler syndrome protein Kindlin-1 is mainly expressed in adult tissues originating from ectoderm/endoderm. Sci China Life Sci 58, 432–441.
Zhang, Y.J., Tu, Y.Z., Gkretsi, V., and Wu, C.Y. (2006). Migfilin interacts with vasodilator-stimulated phosphoprotein (VASP) and regulates VASP localization to cell-matrix adhesions and migration. J Biol Chem 281, 12397–12407.
Author information
Authors and Affiliations
Corresponding author
Additional information
This article is published with open access at link.springer.com
Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
Electronic supplementary material
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
About this article
Cite this article
Qi, L., Yu, Y., Chi, X. et al. Depletion of Kindlin-2 induces cardiac dysfunction in mice. Sci. China Life Sci. 59, 1123–1130 (2016). https://doi.org/10.1007/s11427-016-0025-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-016-0025-0