Gap Junction Remodeling in Hypertrophied Left Ventricles of Aortic-banded Rats: Prevention by Angiotensin II Type 1 Receptor Blockade

doi:10.1006/jmcc.2000.1293

Journal of Molecular and Cellular Cardiology

Volume 33, Issue 2, February 2001, Pages 219-231

https://doi.org/10.1006/jmcc.2000.1293 Get rights and content

Abstract

Remodeling of gap-junctional organization in hypertrophied left ventricle (LV) in response to pressure overload in rats induced by abdominal aorta banding was investigated by immunoconfocal and electron microscopy. Eight to 12 weeks after banding, rats developed significant LV hypertrophy. In contrast to control LV myocytes, which showed connexin43 (Cx43) labeling largely confined to the intercalated disks, LV myocytes from aortic-banded rats showed dispersion of punctate Cx43 labeling over the entire cell surface. In LV tissues sectioned longitudinally, the proportion of Cx43 label at the intercalated disk decreased significantly (control, 0.87 v aortic-banded, 0.62). En-face views of intercalated disks of hypertrophied myocardium revealed a reduction of Cx43 gap junctions in the disk center, giving rise to a significant decrease in the proportion of the disk occupied by gap-junctional membrane (control, 0.32 v aortic-banded, 0.24). Electron microscopy of hypertrophied LV tissue revealed that Cx43-containing gap junctions were frequently displaced from their usual locations to form side-to-side contacts distant from the disk, and also appeared as annular profiles. In aortic-banded rats treated with the angiotensin II (AII) type 1 receptor (AT1) antagonist, losartan (10 mg/kg/day, 11 weeks) not only LV hypertrophy, but also the gap junction disorganization was markedly reduced. These results suggest that LV hypertrophy induced by pressure overload is associated with Cx43 gap junction disorganization and that AII may play an important role either directly or indirectly in gap-junctional remodeling.

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Citation Excerpt :
Though we expected to find an increase in such lateralization in the Xin−/− TAC animals compared to the WT, we instead found multiple ectopic spot-like localizations of connexin43 in cells of TAC-treated animals of both genotypes (Supplementary Fig. S4, asterisks). Such non-ID localizations have been observed before, associated with the membrane of cells after TAC in WT rats [56]. This suggests that TAC, in general, leads to a very strong effect on connexin43 localization even in WT mice, therefore potentially masking more subtle differences between the two genotypes.
Pressure overload induces cardiac remodeling involving both the contractile machinery and intercalated disks (IDs). Filamin C (FlnC) and Xin actin-binding repeat-containing proteins (XIRPs) are multi-adapters localizing in IDs of higher vertebrates. Knockout of the gene encoding Xin (Xirp1) in mice leads to a mild cardiac phenotype with ID mislocalization. In order to amplify this phenotype, we performed transverse aortic constriction (TAC) on control and Xirp1-deficient mice. TAC induced similar left ventricular hypertrophy in both genotypes, suggesting that the lack of Xin does not lead to higher susceptibility to cardiac overload. However, in both genotypes, FlnC appeared in “streaming” localizations across multiple sarcomeres proximal to the IDs, suggesting a remodeling response. Furthermore, FlnC-positive areas of remodeling, reminiscent of sarcomeric lesions previously described for skeletal muscles (but so far unreported in the heart), were also observed. These adaptations reflect a similarly strong effect of the pressure induced by TAC in both genotypes. However, 2 weeks post-operation TAC-treated knockout hearts had reduced levels of connexin43 and slightly increased incidents of ventricular tachycardia compared to their wild-type (WT) counterparts. Our findings highlight the FlnC-positive sarcomeric lesions and ID-proximal streaming as general remodeling responses in cardiac overload-induced hypertrophy.
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2016, Journal of Biological Chemistry
Connexin43 (Cx43) assembly and degradation, the regulation of electrical and metabolic coupling, as well as modulating the interaction with other proteins, involve phosphorylation. Here, we identified and characterized the biological significance of a novel tyrosine kinase that phosphorylates Cx43, tyrosine kinase 2 (Tyk2). Activation of Tyk2 led to a decrease in Cx43 gap junction communication by increasing the turnover rate of Cx43 from the plasma membrane. Tyk2 directly phosphorylated Cx43 residues Tyr-247 and Tyr-265, leading to indirect phosphorylation on residues Ser-279/Ser-282 (MAPK) and Ser-368 (PKC). Although this phosphorylation pattern is similar to what has been observed following Src activation, the response caused by Tyk2 occurred when Src was inactive in NRK cells. Knockdown of Tyk2 at the permissive temperature (active v-Src) in LA-25 cells decreased Cx43 phosphorylation, indicating that although activation of Tyk2 and v-Src leads to phosphorylation of the same Cx43CT residues, they are not identical in level at each site. Additionally, angiotensin II activation of Tyk2 increased the intracellular protein level of Cx43 via STAT3. These findings indicate that, like Src, Tyk2 can also inhibit gap junction communication by phosphorylating Cx43.
Role of connexin 43 in cardiovascular diseases
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Gap junctions (GJs) channels provide the basis for intercellular communication in the cardiovascular system for maintenance of the normal cardiac rhythm, regulation of vascular tone and endothelial function as well as metabolic interchange between the cells. They allow the transfer of small molecules and may enable slow calcium wave spreading, transfer of “death” or of “survival” signals. In the cardiomyocytes the most abundant isoform is Connexin 43 (Cx43). Alterations in Cx43 expression and distribution were observed in myocardium disease; i.e. in hypertrophic cardiomyopathy, heart failure and ischemia. Recent reports suggest the presence of Cx43 in the mitochondria as well, at least in the inner mitochondrial membrane, where it plays a central role in ischemic preconditioning. In this review, the current knowledge on the relationship between the remodeling of cardiac gap junctions and cardiac diseases are summarized.

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^☆: Please address all correspondence to: Yoshiko Takagishi, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan. Tel: +81-52-789-3888; Fax: +81-52-789-3876; E-mail: [email protected]

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Regular ArticleGap Junction Remodeling in Hypertrophied Left Ventricles of Aortic-banded Rats: Prevention by Angiotensin II Type 1 Receptor Blockade☆

Abstract

Am J Cardiology

J Mol Cell Cardiol

J Am Coll Cardiol

Precursors of sudden coronary death: factors related to the incidence of sudden death

Circulation

Cardiac gap junctions

In Fozzard HA, Haber E, Jennings RB, Katz AM, Morgan HE (eds). The Heart and Cardiovascular System, II. New York: Raven Press

Connexins in mammalian heart function

Bio Essays

Cardiovascular disease

In Cardew G (ed). Gap Junction-mediated Intercellular Signaling in Health and Disease, Novartis Foundation Symposium. 219. London: Novartis Foundation

Mechanisms of remodeling of gap junction distributions and the development of anatomic substrates of arrhythmias

Cardiovasc Res

Stage-dependent changes in membrane currents in rats with monocrotaline-induced right ventricular hypertrophy

Am J Physiol

Remodeling of gap junctional coupling in hypertrophied right ventricles of rats with monocrotaline-induced pulmonary hypertension

Circ Res

Altered patterns of cardiac intercellular junction distribution in hypertrophic cardiomyopathy

Heart

Altered patterns of gap junction distribution in ischemic heart disease: an immunohistochemical study of human myocardium using laser scanning confocal microscopy

Am J Pathology

Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia

Circulation

Downregulation of immunodetectable connexin43 and decreased gap junction size in the pathogenesis of chronic hibernation in the human left ventricle

Circulation

Gap junctions in cardiovascular disease

Circ Res

Regular Article
Gap Junction Remodeling in Hypertrophied Left Ventricles of Aortic-banded Rats: Prevention by Angiotensin II Type 1 Receptor Blockade☆