Sarcolemmal Ca2+ transport activities in cardiac hypertrophy caused by pressure overload

Nakanishi, H; Makino, Naoki; Hata, Tomoko; Matsui, Hiroki; Yano, Keiji; Yanaga, Takashi

doi:10.1152/ajpheart.1989.257.2.h349

Cited by 31 publications

(9 citation statements)

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“…Alteration to the kinetics and activity of the Na-pump is an alternative possibility to explain the raised [Na + ] i . Reduced pump activity has been described in spontaneously hypertensive rats [19] and is consistent with the slowed recovery from a raised [Na + ] i recorded in these experiments. The time constant of recovery (τ) of [Na + ] i and pH i is larger in multicellular tissue than in single cells [4] due to diffusion constraints in the former.…”

Section: Discussionsupporting

confidence: 90%

Intracellular sodium and contractile function in hypertrophied human and guinea-pig myocardium

Gray

McIntyre

Sheridan

et al. 2001

Pflügers Arch - Eur J Physiol

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We tested the hypothesis that in left ventricular myocardial hypertrophy (LVH) the positive staircase effect is impaired and is related to a raised intracellular [Na+] ([Na+]i). Human myocardial specimens were obtained from patients undergoing mitral and aortic valve surgery, the latter group had LVH. LVH was induced in guinea-pigs by ascending aortic constriction. The extent of hypertrophy was quantified by measuring myocyte cross-section area, echocardiographic mass (in humans) and heart-to-body weight ratio (in guinea-pigs). The response to increasing stimulation frequency was expressed as the ratio of tension generated at 1.6 and 0.8 Hz (T1.6/0.8); ratios greater and less than 1.0 equate with positive and negative force/frequency relationships respectively. [Na+]i was measured using ion-selective microelectrodes. In human and guinea-pig myocardium T1.6/0.8 values decreased and [Na+]i increased with hypertrophy. For guinea-pig myocardium T1.6/0.8 decreased from 1.39 +/- 0.05 to 1.02 +/- 0.05 and [Na+]i increased from 7.3 +/- 1.4 to 12.1 +/- 1.3 mM in LVH. There was a close relationship between the reduction of T1.6/0.8 and increase of [Na+]i which was also observed when the [Na+]i was increased with strophanthidin in normal myocardium. The recovery of a raised [Na+]i after an acute acidosis was slowed in hypertrophied myocardium and stabilised at a higher level, suggesting that the membrane mechanisms that regulate [Na+]i are reset.

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Section: Discussionsupporting

confidence: 90%

Intracellular sodium and contractile function in hypertrophied human and guinea-pig myocardium

Gray

McIntyre

Sheridan

et al. 2001

Pflügers Arch - Eur J Physiol

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“…49 Normally the Na ϩ /K ϩ -ATPase would extrude accumulated Na ϩ , but its activity has been shown to be reduced in hypertrophy. 50 High [Na ϩ ] i may be hypertrophic by 2 possible mechanisms. First, inhibition of the plasma membrane Na ϩ / Ca 2ϩ exchanger (NCX), normally responsible for maintenance of low [Ca 2ϩ ] i .…”

Section: Discussionmentioning

confidence: 99%

Molecular Basis for Angiotensin II-Induced Increase of Chloride/Bicarbonate Exchange in the Myocardium

Álvarez

Fujinaga

Casey

2001

Circulation Research

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Abstract-Plasma membrane anion exchangers (AEs) regulate myocardial intracellular pH (pH i ) by Na ϩ -independent Cl Ϫ /HCO 3 Ϫ exchange. Angiotensin II (Ang II) activates protein kinase C (PKC) and increases anion exchange activity in the myocardium. Elevated anion exchange activity has been proposed to contribute to the development of cardiac hypertrophy. Our Northern blots showed that adult rat heart expresses AE1, AE2, AE3fl, and AE3c. Activity of each AE isoform was individually measured by following changes of pH i , associated with bicarbonate transport, in transfected HEK293 cells. Exposure to the PKC activator, PMA (150 nmol/L), increased the transport activity of only the AE3fl isoform by 50Ϯ11% (PϽ0.05, nϭ6), consistent with the increase observed in intact myocardium. Cotransfection of HEK293 cells with AE3fl and AT1 a -Ang II receptors conferred sensitivity of anion transport to Ang II (500 nmol/L), increasing the transport activity by 39Ϯ3% (PϽ0.05, nϭ4). PKC inhibition by chelerythrine (10 mol/L) blocked the PMA effect. To identify the PKC-responsive site, 7 consensus PKC phosphorylation sites of AE3fl were individually mutated to alanine. Mutation of serine 67 of AE3 prevented the PMA-induced increase of anion transport activity. Inhibition of MEK1/2 by PD98059 (50 mol/L) did not affect the response of AE3fl to Ang II, indicating that PKC directly phosphorylates AE3fl. We conclude that following Ang II stimulation of cells, PKC⑀ phosphorylates serine 67 of the AE3 cytoplasmic domain, inducing the Ang II-induced increase in anion transport observed in the hypertrophic myocardium. Key Words: hypertrophy Ⅲ anion exchange Ⅲ pH regulation Ⅲ angiotensin II Ⅲ protein kinase C I ntracellular pH (pH i ) regulates excitation-contraction coupling in cardiac cells through ionic conductances, 1 metabolic pathways, 2 Ca 2ϩ homeostasis, 3 contractility, 4 and electrical conduction. 5 Four well-characterized membrane ion transporters regulate cardiomyocyte pH i . Acid loads activate Na ϩ /H ϩ exchange (NHE) and Na ϩ /HCO 3 Ϫ symport (NBC), 6,7 whereas after an alkaline load, Na ϩ -independent Cl Ϫ /HCO 3 Ϫ exchangers (AEs) 8 and a second dual acid-loading mechanism 9 are activated. Anion exchange proteins, which facilitate the reversible electroneutral exchange of Cl Ϫ for HCO 3 Ϫ across the plasma membrane, regulate pH i , intracellular chloride concentration, bicarbonate metabolism and cell volume. The AE family comprises 3 members: AE1, AE2, and AE3. 10 Heart and retina coexpress 2 different isoforms of AE3, AE3 full length (AE3fl, the most abundant AE protein expressed in the brain) and AE3 cardiac (AE3c), which result from alternative promoter usage. 11,12 Rat AE3fl is 1227 amino acids long and AE3c contains 1034 amino acids. The C-terminal 957 amino acids of both polypeptides are identical, but the AE3c protein contains a unique N-terminal sequence of 73 amino acids, which replaces the unique first 270 amino acids of the AE3fl form. 11 A truncated form of AE1 was recently characterized in rat ventricular my...

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“…For instance, an increased NCX activity [7], [8] and either a decrease, increase or no change in SERCA2a expression/activity was described in young SHR [9]–[11]. At this stage, phosphorylation of PLN has been shown to be increased at the Ca 2+ -calmodulin-dependent kinase (CaMKII) site, Thr 17 [9], [11], [12].…”

Section: Introductionmentioning

confidence: 99%

Increased Na+/Ca2+ Exchanger Expression/Activity Constitutes a Point of Inflection in the Progression to Heart Failure of Hypertensive Rats

et al. 2014

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Spontaneously hypertensive rat (SHR) constitutes a genetic model widely used to study the natural evolution of hypertensive heart disease. Ca2+-handling alterations are known to occur in SHR. However, the putative modifications of Ca2+-handling proteins during the progression to heart failure (HF) are not well established. Moreover, the role of apoptosis in SHR is controversial. We investigated intracellular Ca2+, Ca2+-handling proteins and apoptosis in SHR vs. control Wistar rats (W) from 3 to 15 months (mo). Changes associated with the transition to HF (i.e. lung edema and decrease in midwall fractional shortening), occurred at 15 mo in 38% of SHR (SHRF). In SHRF, twitch and caffeine-induced Ca2+ transients, significantly decreased relative to 6/9 mo and 15 mo without HF signs. This decrease occurred in association with a decrease in the time constant of caffeine-Ca2+ transient decay and an increase in Na+/Ca2+ exchanger (NCX) abundance (p<0.05) with no changes in SERCA2a expression/activity. An increased Ca2+-calmodulin-kinase II activity, associated with an enhancement of apoptosis (TUNEL and Bax/Bcl2) was observed in SHR relative to W from 3 to 15 mo. Conclusions: 1. Apoptosis is an early and persistent event that may contribute to hypertrophic remodeling but would not participate in the contractile impairment of SHRF. 2. The increase in NCX expression/activity, associated with an increase in Ca2+ efflux from the cell, constitutes a primary alteration of Ca2+-handling proteins in the evolution to HF. 3. No changes in SERCA2a expression/activity are observed when HF signs become evident.

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Sarcolemmal Ca2+ transport activities in cardiac hypertrophy caused by pressure overload

Cited by 31 publications

References 0 publications

Intracellular sodium and contractile function in hypertrophied human and guinea-pig myocardium

Intracellular sodium and contractile function in hypertrophied human and guinea-pig myocardium

Molecular Basis for Angiotensin II-Induced Increase of Chloride/Bicarbonate Exchange in the Myocardium

Increased Na+/Ca2+ Exchanger Expression/Activity Constitutes a Point of Inflection in the Progression to Heart Failure of Hypertensive Rats

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