Caveolin modulates integrin function and mechanical activation in the cardiomyocyte

Israeli-Rosenberg, Sharon; Chen, Chao; Li, Ruixia; Deussen, Daniel N.; Niesman, Ingrid R.; Okada, Hideshi; Patel, Hemal H.; Roth, David M.; Ross, Robert S.

doi:10.1096/fj.13-243139

Cited by 24 publications

(20 citation statements)

References 58 publications

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“…Phosphorylation of caveolin-1 at Tyr14 is involved in the integrin-regulated caveolae trafficking and also in signaling at focal adhesions in migrating cells (31). ␤ 1 -Integrin is also an important component of caveolae membranes (28,16,40). In the present study, SW therapy enhanced protein levels of ␤ 1 -integrin, but not those of caveolin-1, and enhanced the phosphorylation state of caveolin-1 and ␤ 1 -integrin activity.…”

Section: Discussionsupporting

confidence: 48%

Molecular mechanisms of the angiogenic effects of low-energy shock wave therapy: roles of mechanotransduction

Hatanaka

Ito

Shindo

et al. 2016

American Journal of Physiology-Cell Physiology

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H. Molecular mechanisms of the angiogenic effects of low-energy shock wave therapy: roles of mechanotransduction. Am J Physiol Cell Physiol 311: C378 -C385, 2016. First published July 13, 2016; doi:10.1152/ajpcell.00152.2016.-We have previously demonstrated that low-energy extracorporeal cardiac shock wave (SW) therapy improves myocardial ischemia through enhanced myocardial angiogenesis in a porcine model of chronic myocardial ischemia and in patients with refractory angina pectoris. However, the detailed molecular mechanisms for the SW-induced angiogenesis remain unclear. In this study, we thus examined the effects of SW irradiation on intracellular signaling pathways in vitro. Cultured human umbilical vein endothelial cells (HUVECs) were treated with 800 shots of low-energy SW (1 Hz at an energy level of 0.03 mJ/mm 2 ). The SW therapy significantly upregulated mRNA expression and protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). The SW therapy also enhanced phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2) and Akt. Furthermore, the SW therapy enhanced phosphorylation of caveolin-1 and the expression of HUTS-4 that represents ␤1-integrin activity. These results suggest that caveolin-1 and ␤1-integrin are involved in the SW-induced activation of angiogenic signaling pathways. To further examine the signaling pathways involved in the SW-induced angiogenesis, HUVECs were transfected with siRNA of either ␤ 1-integrin or caveolin-1. Knockdown of either caveolin-1 or ␤ 1-integrin suppressed the SW-induced phosphorylation of Erk1/2 and Akt and upregulation of VEGF and eNOS. Knockdown of either caveolin-1 or ␤1-integrin also suppressed SW-induced enhancement of HUVEC migration in scratch assay. These results suggest that activation of mechanosensors on cell membranes, such as caveolin-1 and ␤1-integrin, and subsequent phosphorylation of Erk and Akt may play pivotal roles in the SW-induced angiogenesis. shock wave; mechanotransduction; angiogenesis; caveolin-1; ␤1-integrin SHOCK WAVES (SW) have been clinically introduced for lithotripsy since the 1980s; urinary stones are broken up by highenergy SW (7). The waveform of an SW is similar to that of a blast wave, which is composed of discontinuous compression of leading shock propagating with supersonic speed, subsequent rarefaction, and negative pressure (27). Over the past 20 years, low-energy SW therapy has also been put into clinical application (3,17). We have previously demonstrated that low-energy SW (about 10% of the energy used for urolithotripsy treatment) significantly upregulated vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells (HUVECs) (25). Low-energy SW therapy has also been reported to enhance nitric oxide (NO) production via activation of endothelial NO synthase (eNOS) in vitro (23,24). We have demonstrated that extracorporeal low-energy cardiac SW therapy enhances angiogenesis and contractile function in a porcine model of chronic myocardial isc...

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Section: Discussionsupporting

confidence: 48%

Molecular mechanisms of the angiogenic effects of low-energy shock wave therapy: roles of mechanotransduction

Hatanaka

Ito

Shindo

et al. 2016

American Journal of Physiology-Cell Physiology

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“…To investigate whether loss of CM Tln2 and the subsequent compensatory increase in Tln1 expression causes changes in integrin activation, we stained heart tissue with the 9EG7 antibody that specifically recognizes the activated form of the β1-integrin subunit (26,27). Consistent with the reduction of total β1-integrin expression in CMs, the levels of activated β1 integrin detected by the 9EG7 antibody were also reduced in Tln2KO heart compared with WT.…”

Section: Integrins and Proteins Of The Integrin Complex Are Altered Imentioning

confidence: 88%

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

Manso

Okada

Sakamoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Continuous contraction-relaxation cycles of the heart require strong and stable connections of cardiac myocytes (CMs) with the extracellular matrix (ECM) to preserve sarcolemmal integrity. CM attachment to the ECM is mediated by integrin complexes localized at the muscle adhesion sites termed costameres. The ubiquitously expressed cytoskeletal protein talin (Tln) is a component of muscle costameres that links integrins ultimately to the sarcomere. There are two talin genes, Tln1 and Tln2. Here, we tested the function of these two Tln forms in myocardium where Tln2 is the dominant isoform in postnatal CMs. Surprisingly, global deletion of Tln2 in mice caused no structural or functional changes in heart, presumably because CM Tln1 became up-regulated. Tln2 loss increased integrin activation, although levels of the musclespecific β1D-integrin isoform were reduced by 50%. With this result, we produced mice that had simultaneous loss of both CM Tln1 and Tln2 and found that cardiac dysfunction occurred by 4 wk with 100% mortality by 6 mo. β1D integrin and other costameric proteins were lost from the CMs, and membrane integrity was compromised. Given that integrin protein reduction occurred with Tln loss, rescue of the phenotype was attempted through transgenic integrin overexpression, but this could not restore WT CM integrin levels nor improve heart function. Our results show that CM Tln2 is essential for proper β1D-integrin expression and that Tln1 can substitute for Tln2 in preserving heart function, but that loss of all Tln forms from the heart-muscle cell leads to myocyte instability and a dilated cardiomyopathy.T he heart and all of its attendant cells, particularly the contracting cardiac myocytes (CMs), are constantly subjected to high forces. Proper linkage between the cellular cytoskeleton, the cell membrane (termed the sarcolemma in muscle cells), and the extracellular matrix (ECM) is necessary for synchronized force distribution among the cells of the myocardium (1-3). When these linkages are disturbed, forces may be distributed abnormally, cardiac muscle can be injured, and therefore whole-heart function can become abnormal. A number of intracellular proteins and membrane receptors have been found to be crucial for organizing this interactive arrangement between the intracellular CM environment and the surrounding ECM. The integrin family of adhesion receptors are key proteins operative in this response (4). Integrins are a large family of 18 α-subunits and 8 β-subunits, which heterodimerize noncovalently, forming over 24 unique transmembrane receptors on virtually all cells, including CMs. They bind directly to ECM proteins via their proportionally large extracellular domains, and their short cytoplasmic tails assist with organizing a large multiprotein complex that connects integrins to the actin cytoskeleton and may transduce signals to a range of downstream pathways. With these connections, integrins are recognized as key mechanotransducers, converting mechanical perturbations to biochemical signals (...

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“…Integrin has been demonstrated to mediate mechanotransduction in various types of cells, including neurons, fibroblasts, epithelial cells, cardiomyocytes, and tendon stem/progenitor cells (Ye et al, 2010; Zhang et al, 2011; Moore et al, 2012; Fiore et al, 2015; Israeli-Rosenberg et al, 2015; Sun X. et al, 2016; Sun Z. et al, 2016; Wang et al, 2016). Recent studies have also shown that integrin plays a vital role in cell migration; the migration of SCs on astrocytes was shown to be clearly integrin-dependent (Nodari et al, 2007; Afshari et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Superparamagnetic Iron Oxide Nanoparticle-Mediated Forces Enhance the Migration of Schwann Cells Across the Astrocyte-Schwann Cell Boundary In vitro

Huang

Xia

Liu

et al. 2017

Front. Cell. Neurosci.

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Schwann cells (SCs) are one of the most promising cellular candidates for the treatment of spinal cord injury. However, SCs show poor migratory ability within the astrocyte-rich central nervous system (CNS) environment and exhibit only limited integration with host astrocytes. Our strategy for improving the therapeutic potential of SCs was to magnetically drive SCs to migrate across the astrocyte-SC boundary to intermingle with astrocytes. SCs were firstly magnetized with poly-L-lysine-coated superparamagnetic iron oxide nanoparticles (SPIONs). Internalization of SPIONs showed no effect upon the migration of SCs in the absence of a magnetic field (MF). In contrast, magnetized SCs exhibited enhanced migration along the direction of force in the presence of a MF. An inverted coverslip assay showed that a greater number of magnetized SCs migrated longer distances onto astrocytic monolayers under the force of a MF compared to other test groups. More importantly, a confrontation assay demonstrated that magnetized SCs intermingled with astrocytes under an applied MF. Furthermore, inhibition of integrin activation reduced the migration of magnetized SCs within an astrocyte-rich environment under an applied MF. Thus, SPION-mediated forces could act as powerful stimulants to enhance the migration of SCs across the astrocyte-SC boundary, via integrin-mediated mechanotransduction, and could represent a vital way of improving the therapeutic potential of SCs for spinal cord injuries.

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Caveolin modulates integrin function and mechanical activation in the cardiomyocyte

Cited by 24 publications

References 58 publications

Molecular mechanisms of the angiogenic effects of low-energy shock wave therapy: roles of mechanotransduction

Molecular mechanisms of the angiogenic effects of low-energy shock wave therapy: roles of mechanotransduction

Loss of mouse cardiomyocyte talin-1 and talin-2 leads to β-1 integrin reduction, costameric instability, and dilated cardiomyopathy

Superparamagnetic Iron Oxide Nanoparticle-Mediated Forces Enhance the Migration of Schwann Cells Across the Astrocyte-Schwann Cell Boundary In vitro

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