Decreased Ca2+extrusion via Na+/Ca2+exchange in epicardial left ventricular myocytes during compensated hypertrophy

Fowler, Mark R.; Naz, James R.; Graham, Mark; Bru–Mercier, Gilles; Harrison, Simon; Orchard, Clive H.

doi:10.1152/ajpheart.01069.2004

Cited by 22 publications

(27 citation statements)

References 35 publications

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“…Although the heart weight to body weight (HW/BW) ratio did not increase significantly in the SHR, left ventricular weight to body weight (LV/BW) ratio did increase significantly, and ventricular myocytes from SHRs exhibited significantly increased cell capacitance (+21%) compared to normotensive control (WKY) cells, consistent with the cellular hypertrophy previously reported in this model [15] (see Fig. 1).…”

Section: Discussionsupporting

confidence: 86%

“…Thus, I Ca density in the SHR appears to be unaltered at this stage of hypertrophy. Given the central role of I Ca and the t-tubules in the synchronisation of Ca 2+ release (see 'Introduction'), the apparent parallel increases in the t-tubule system, and I Ca in the present study may explain why the Ca 2+ transient remains synchronised in the SHR [15], although this synchronisation may be lost subsequently as hypertrophy progresses to heart failure with partial loss of the t-system [16,19].…”

Section: Ca In Intact Wky and Shr Cellsmentioning

confidence: 67%

“…* denotes P<0.05 vs intact cells of same strain. tot total, sl sarcolemma, tt t-tubule Morphology, cell capacitance and detubulation The present study investigated the distribution of I Ca during mild compensated hypertrophy in the SHR, a model that has been used extensively to investigate hypertrophic remodelling [7,8,15,21,24]. Compared to most surgically induced hypertrophy models, hypertrophy in the SHR, which is secondary to hypertension, develops more slowly, mimicking the speed of onset in humans.…”

Section: Discussionmentioning

confidence: 99%

“…Changes in cellular Ca 2+ handling are thought to underlie the cardiac cell remodelling that occurs in response to hypertension, which results in cellular hypertrophy and an altered Ca 2+ transient phenotype [7,15,21]. I Ca , which is located predominantly in the t-tubules, is central to Ca 2+ cycling in cardiac myocytes and has been reported to change during hypertrophic remodelling.…”

Section: Introductionmentioning

confidence: 99%

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Cellular distribution of calcium current is unaltered during compensated hypertrophy in the spontaneously hypertensive rat

Fowler

Orchard

Harrison

2006

Pflugers Arch - Eur J Physiol

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Changes in cellular calcium (Ca(2+)) handling are thought to underlie the altered contraction that occurs during cardiac hypertrophy and failure. Recent work has highlighted the importance of t-tubules in the control of intracellular Ca(2+). The present study was performed to investigate whether changes in the distribution of I (Ca) between the surface and t-tubule membranes might contribute to the altered Ca(2+) handling observed during compensated hypertrophy in the spontaneously hypertensive rat (SHR). Experiments were performed on ventricular myocytes isolated from 5-month-old SHR and normotensive Wistar-Kyoto (WKY) control rats. Osmotic shock using formamide was used to disrupt the t-tubular system and the whole-cell patch clamp technique used to monitor I (Ca) in the presence and absence of t-tubules. Membrane capacitance and I (Ca) were greater in control SHR than WKY myocytes; following detubulation, cell capacitance and I (Ca) both decreased and were no longer significantly different in the two cell types. The density of I (Ca) was not significantly different in control SHR and WKY cells or in detubulated myocytes from the two species. These data suggest that the distribution of I (Ca) is unchanged in SHR myocytes compared to WKY controls; I (Ca) density in the t-tubules was 1.2-fold greater than in the sarcolemma in both strains. These data also imply that the increase in surface area in SHR myocytes is due principally to an increase in t-tubular area, which is accompanied by an approximately equivalent increase in I (Ca), so that the density of I (Ca) at the cell surface and in the t-tubules remains the same. These changes would be expected to retain cell function and synchronicity of Ca(2+) release in the SHR at this stage of compensated hypertrophy.

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Section: Discussionsupporting

confidence: 86%

Section: Ca In Intact Wky and Shr Cellsmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cellular distribution of calcium current is unaltered during compensated hypertrophy in the spontaneously hypertensive rat

Fowler

Orchard

Harrison

2006

Pflugers Arch - Eur J Physiol

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“…This null effect may reflect attenuation of calcium cycling pathways ordinarily upregulated in cardiac hypertrophy. 24,25 …”

Section: Ltcc ␤ 2 Knockdown Does Not Impair Systolic Performancementioning

confidence: 99%

Gene Therapy to Inhibit the Calcium Channel β Subunit

Cingolani

Correa

Kizana

et al. 2007

Circulation Research

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Abstract-CalciumKey Words: hypertrophy Ⅲ calcium Ⅲ gene therapy C alcium cycling in the heart is triggered by calcium influx through L-type calcium channels. 1 Such calcium channels are present and functionally important not only in cardiac myocytes but also in diverse smooth muscles and in neurons. Enhancement of calcium-regulated signaling pathways contributes to the development of left ventricular hypertrophy (LVH). 2 Thus, calcium channel inhibition represents a logical approach to treatment of LVH. Gene therapy allows for more directed and organ-specific delivery and thus may avoid undesired systemic effects, which may account in part for the limited clinical benefit observed with these agents. 3 L-type calcium channels are heteromultimers of various subunits. The accessory ␤ subunit (LTCC␤) not only favors the trafficking of the calcium channel to the surface membrane, but also enhances the probability of channel opening 4 -7 resulting in increased calcium current. Interestingly, upregulation of a splice variant of the LTCC␤ (␤ 2a ) has been previously described in failing human cardiomyocytes. 8 Whether or not ␤ subunits are upregulated in hypertrophy, we hypothesized that suppression of LTCC␤ might represent an attractive means to inhibit calcium influx, attenuate calciumdependent signaling and ultimately prevent or treat LVH.Using RNA interference technology to selectively modulate the expression of the gene of interest, we studied the physiological effects of LTCC␤ modulation in native cardiac cells, and the effects in a cellular model of hypertrophy. To further investigate the effects of LTCC␤ downregulation in cardiac hypertrophy, we performed in vivo gene transfer of an "advanced" generation lentiviral vector capable of permanently modulating the expression of LTCC␤. A rat pressureoverload LVH model was implemented to test the potential beneficial effect of modulating the expression of the L-type calcium channel accessory ␤ subunit. Materials and MethodsFor a detailed Materials and Methods, please see the online data supplement available at http://circres.ahajournals.org. Short Hairpin RNA Design and Vector ProductionA series of short interference RNA duplexes (siRNAs) against the D2 conserved domain 9 of LTCC␤ were designed according to published algorithms 10 and synthesized. The three most active sequences and one scrambled, nonsilencing (NS) sequence were designed into a short hairpin RNA (shRNA) oligonucleotide. These three active shRNAs and one NS-shRNA sequence were screened Original

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N-3 vs. n-6 fatty acids differentially influence calcium signalling and adhesion of inflammatory activated monocytes: impact of lipid rafts

Schaefer

Schifferings

et al. 2016

Inflamm. Res.

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Decreased Ca²⁺extrusion via Na⁺/Ca²⁺exchange in epicardial left ventricular myocytes during compensated hypertrophy

Cited by 22 publications

References 35 publications

Cellular distribution of calcium current is unaltered during compensated hypertrophy in the spontaneously hypertensive rat

Cellular distribution of calcium current is unaltered during compensated hypertrophy in the spontaneously hypertensive rat

Gene Therapy to Inhibit the Calcium Channel β Subunit

N-3 vs. n-6 fatty acids differentially influence calcium signalling and adhesion of inflammatory activated monocytes: impact of lipid rafts

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