β1 Integrins Modulate β-Adrenergic Receptor–Stimulated Cardiac Myocyte Apoptosis and Myocardial Remodeling

Krishnamurthy, Prasanna; Subramanian, Vijay; Singh, Mahipal; Singh, Krishna

doi:10.1161/01.hyp.0000258703.36986.13

Cited by 87 publications

(92 citation statements)

References 47 publications

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“…The finding of a downstream activation of p38 MAPK, ERK1/2 and JNK in dependence on PKA following isoprenaline application is in good accordance with other findings in adult rats (Zhang et al 2005) or in neonatal rat cardiomyocytes (Zou et al 1999;Zheng et al 2000;Fan et al 2006;Krishnamurthy et al 2007).…”

Section: Role Of α-And β-Adrenoceptors In the Acute Regulation Of Gapsupporting

confidence: 92%

Adrenergic control of cardiac gap junction function and expression

Salameh

Dhein²

2011

Naunyn-Schmied Arch Pharmacol

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Electrical intercellular communication in the heart allows the propagation of an action potential from cell to cell. This is realized by low-ohmic cell-to-cell channels, the gap junction channels, which are dodecameric proteins consisting of two hexameric hemichannels. Each of the neighbouring cell provides one hemichannel, which consists of six connexins. In the heart, the connexin isoforms Cx43, Cx40 and Cx45 are present with Cx43 being the most abundant isoform. This intercellular communication is regulated acutely by control of the gap junction conductance and chronically by control of the connexin expression. The short half-life time of Cx43 indicates the permanent adaptation of cell communication to the actual requirements. β-Adrenoceptor stimulation enhances Cx40- but reduces Cx45-conductance, while Cx43 channels in most species do not seem to be acutely affected by β-adrenoceptor signalling. In contrast, chronic exposure to β-adrenergic stimulants activates protein kinase A and the mitogenic-activated protein kinase cascade (including protein 38 (p38), mitogenic-activated protein kinase kinase 1, extracellular signal-regulated kinase (ERK)1/2 and c-JUN NH(2) terminal kinase (JNK)), the calcineurin pathway, translocation of activator protein 1 (AP1), CRE-binding protein and nuclear factor of activated T cells, finally leading to enhanced Cx43-mRNA and Cx43-protein expression together with Cx43 phosphorylation, but does not affect Cx40. α-Adrenoceptors also play a role in controlling cardiac intercellular communication: α-adrenergic stimulation acutely uncouples the cells, while a chronic stimulation enhances Cx43 expression via protein kinase C, p38, ERK1/2, JNK, c-fos and AP1, but does not alter Cx40 expression. While general cardiac protein synthesis, e.g. of β-actin, is controlled via α(1A)-adrenoceptors, Cx43 expression is regulated via α(1D)-adrenoceptors. However, α-adrenoceptor density in the heart varies among species, with high abundance in rat heart and low in human heart. Acute α-adrenergic stimulation, e.g. during ischemia, can lead to uncoupling and facilitates re-entrant arrhythmia. Chronic adrenergic upregulation of Cx43 expression seems to be involved in cardiac hypertrophy. In maladaptive hypertrophy, the enhanced Cx43 is increasingly incorporated in the lateral membrane of the cells rather at the cell poles, which may mean a gap junction disarray. This could-together with a mismatch in cell size and coupling-contribute to arrhythmogenesis. Thus, cardiac adrenoceptors are directly involved in the control of intercellular electrical communication and thus probably are a critical factor in the maintenance of regular cell-to-cell conduction and of the cardiac electrical networking. They probably are involved in the formation of an arrhythmogenic substrate in certain heart diseases.

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Section: Role Of α-And β-Adrenoceptors In the Acute Regulation Of Gapsupporting

confidence: 92%

Adrenergic control of cardiac gap junction function and expression

Salameh

Dhein²

2011

Naunyn-Schmied Arch Pharmacol

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“…sarcolemmal membrane. Despite this, the 50% of β1D-integrin protein remaining in the KO CM is clearly sufficient to maintain normal heart function, consistent with previously published work (22,23).…”

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

confidence: 90%

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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“…Moreover, when periodontal β 1 autoantibodies bind and activate rat atria β 1 -AR, this leads to activation of adenylate cyclase, with an increase in cAMP production that, in turn, involves activation of PKA that ultimately modulates the heart apoptotic pathway. Similar observations have been made in neonatal rat ventricular myocytes and in the myocardium of rats and mice treated with isoproterenol [49,50]. Mitogen-activated protein kinases have important functions as mediators of intracellular signal transduction in the heart.…”

Section: Discussionsupporting

confidence: 76%