Postnatal Loss of Kindlin-2 Leads to Progressive Heart Failure

Abstract

Background The striated muscle costamere, a multi-protein 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 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. Methods and Results 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 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 was associated with enlargement of the heart, and extensive fibrosis. In addition, integrin β1D protein expression was significantly downregulated in adult heart. Conclusions Kindlin-2 is required to maintain integrin β1D protein stability. Postnatal loss of Kindlin-2 from cardiomyocytes leads to progressive heart failure showing the importance of costameric proteins like Kindlin-2 for homeostasis of normal heart function.

Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy

“…Male chimeras were bred with female C57BL/6J mice to generate germline-transmitted BAG3 E455K mice Animal procedures, echocardiography, and hemodynamics. Echocardiography was performed as previously described (60,61). Briefly, mice were anesthetized with 1% isoflurane and underwent echocardiography using a FUJIFILM VisualSonics SonoSite Vevo 2100 ultrasound system blots analysis with antibodies against 14 proteins that had been found to be upregulated in the insoluble fraction of BAG3-CKO mouse hearts.…”

Overview of the Muscle Cytoskeleton

“…16). Cardiac-specific knockout of kindlin-2 results in embryonic lethality, however postnatal cardiac-specific deletion led to fibrosis and heart failure indicating kindlin-2 is essential for integrin function (770). …”

Kindlin-2 Modulates the Survival, Differentiation, and Migration of Induced Pluripotent Cell-Derived Mesenchymal Stromal Cells

“…Kindlin-2 not only modulates inside-out signaling by interacting with integrin β chains [20], but also contributes to outside-in signaling by binding to integrin-linked kinase [21]. More recently, it has been shown that Kindlin-2 can regulate integrin β 1 protein expression in adult cardiomyocytes [22]. Kindlin-2 is also involved in regulating cancer cell invasions with varying functions in different cancer types [23].…”