Continuous Blockade of L-Type Ca2+ Channels Suppresses Activation of Calcineurin and Development of Cardiac Hypertrophy in Spontaneously Hypertensive Rats

Zou, Yunzeng; Yamazaki, Tsutomu; Nakagawa, Keiichi; Yamada, Hideaki; Iriguchi, Norio; Toko, Haruhiro; Takano, Hiroyuki; Akazawa, Hiroshi; Nagai, Ryozo; Komuro, Issei

doi:10.1291/hypres.25.117

Cited by 43 publications

(24 citation statements)

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“…The L-type Ca 2ϩ current (L-current) density was similar in sham-operated WT myocytes compared Figure 7C). It has been reported that the reduction of the L-current by continuous infusion of L-channel blocker 35 or the knockdown of L-channel accessory ␤ subunit 36 channels that open at the resting membrane potential of a HEK293 cell (ie, window current). 37,38 As shown in Figure 8A, 10 mmol/L Ca 2ϩ significantly increased the NFAT-luciferase reporter activity relative to that of cells transfected with control vehicle and T-channel blocker mibefradil effectively blocked NFAT-luciferase activity triggered by calcium.…”

Section: Currents From Acutely Isolated Left Ventricular Myocytesmentioning

confidence: 99%

“…The L-type Ca 2ϩ current (L-current) density was similar in sham-operated WT myocytes compared Figure 7C). It has been reported that the reduction of the L-current by continuous infusion of L-channel blocker 35 or the knockdown of L-channel accessory ␤ subunit 36 alleviates hypertrophic response. Our data rule out the possibility that blunted hypertrophy response in banded Ca v 3.2 Ϫ/Ϫ mice results from the downregulation of L-type Ca 2ϩ currents.…”

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confidence: 99%

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The Ca _V 3.2 T-Type Ca ²⁺ Channel Is Required for Pressure Overload–Induced Cardiac Hypertrophy in Mice

Chiang

Huang

Chieng

et al. 2009

Circulation Research

145

123

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Abstract-Voltage-gated T-type Ca 2ϩ channels (T-channels) are normally expressed during embryonic development in ventricular myocytes but are undetectable in adult ventricular myocytes. Interestingly, T-channels are reexpressed in hypertrophied or failing hearts. It is unclear whether T-channels play a role in the pathogenesis of cardiomyopathy and what the mechanism might be. Here we show that the ␣ 1H voltage-gated T-type Ca 2ϩ channel (Ca v 3.2) is involved in the pathogenesis of cardiac hypertrophy via the activation of calcineurin/nuclear factor of activated T cells (NFAT) pathway. Specifically, pressure overload-induced hypertrophy was severely suppressed in mice deficient for Ca v 3.2 (Ca v 3.2 Ϫ/Ϫ ) but not in mice deficient for Ca v 3.1 (Ca v 3.1 Ϫ/Ϫ ). Angiotensin II-induced cardiac hypertrophy was also suppressed in Ca v 3.2 Ϫ/Ϫ mice. Consistent with these findings, cultured neonatal myocytes isolated from Ca v 3.2 Ϫ/Ϫ mice fail to respond hypertrophic stimulation by treatment with angiotensin II. Together, these results demonstrate the importance of Ca v 3.2 in the development of cardiac hypertrophy both in vitro and in vivo. To test whether Ca v 3.2 mediates the hypertrophic response through the calcineurin/NFAT pathway, we generated Ca v 3.2 Ϫ/Ϫ , NFAT-luciferase reporter mice and showed that NFAT-luciferase reporter activity failed to increase after pressure overload in the Ca v 3.2 Ϫ/Ϫ /NFAT-Luc mice. Our results provide strong genetic evidence that Ca v 3.2 indeed plays a pivotal role in the induction of calcineurin/NFAT hypertrophic signaling and is crucial for the activation of pathological cardiac hypertrophy. H ypertrophic growth and remodeling of the adult heart begin as normal compensatory responses to a variety of physiological and pathological stimuli including exercise, pregnancy, pressure overload, hypertension, myocardial infarction, and primary genetic abnormalities. [1][2][3] Prolonged hypertrophic response may eventually lead to heart failure and death. Pathological hypertrophy is often associated with structural and functional remodeling of the heart. Profound changes in gene expression during pathological cardiac hypertrophy are common, particularly in the case of genes that code for proteins involved in regulating contraction ion channels, for example. 4 Alterations of intracellular Ca 2ϩ handling could lead to abnormal Ca 2ϩ signaling cascades, a phenomenon that has been shown to contribute to the pathogenesis of cardiac hypertrophy and heart failure. 5,6 However, the detailed mechanism of how the cardiac myocytes distinguish Ca 2ϩ transients that occur at every heartbeat from those meant to trigger intracellular hypertrophic signaling remains largely unknown. Intracellular Ca 2ϩ levels could be altered because of either changes in Ca 2ϩ release from intracellular organelles or the influx of extracellular Ca 2ϩ , and in both cases, this could be attributable to the activities of either ligand-or voltage-activated Ca 2ϩ channels. Indeed, ligand-activated Ca 2ϩ channels, such as ...

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Section: Currents From Acutely Isolated Left Ventricular Myocytesmentioning

confidence: 99%

“…The L-type Ca 2ϩ current (L-current) density was similar in sham-operated WT myocytes compared Figure 7C). It has been reported that the reduction of the L-current by continuous infusion of L-channel blocker 35 or the knockdown of L-channel accessory ␤ subunit 36 alleviates hypertrophic response. Our data rule out the possibility that blunted hypertrophy response in banded Ca v 3.2 Ϫ/Ϫ mice results from the downregulation of L-type Ca 2ϩ currents.…”

mentioning

confidence: 99%

The Ca _V 3.2 T-Type Ca ²⁺ Channel Is Required for Pressure Overload–Induced Cardiac Hypertrophy in Mice

Chiang

Huang

Chieng

et al. 2009

Circulation Research

145

123

View full text Add to dashboard Cite

show abstract

“…9) Hayashi, et al 10) also reported that a combination of ARB and nifedipine enhances this effect, and increases the myocardial capillary density. On the other hand, Komuro, et al 11) suggested that long-acting Ca antagonists may prevent cardiac hypertrophy by altering calcineurin activation due to Ca 2+ inflow into the myocardium during the onset and progression of cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Additive Antihypertensive and Antihypertrophic Effects of Long-Acting Ca Blockers in Uncontrolled Hypertensive Patients With Angiotensin-Receptor Blocker Based Treatment

et al. 2009

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SummaryThe aim of the present study was to examine the antihypertensive and antihypertrophic effects of combined treatment with a long-acting calcium antagonist on top of an angiotensin II receptor blocker (ARB) in uncontrolled hypertensive patients. Patients with essential hypertension and a blood pressure > 140/90 mmHg on ARB monotherapy (losartan 50 mg/day or candesartan 8 mg/day) were randomly assigned to a nifedipine controlled release (CR) group (n = 15) or amlodipine group (n = 11). A significant additional antihypertensive effect was noted from 1 month with nifedipine and 2 months with amlodipine. The average daily dose was 25 mg for nifedipine and 5 mg for amlodipine. The cardiothoracic ratio was significantly reduced in both groups after 3 months. Left ventricular wall thickness and left ventricular mass index also decreased. Metabolic parameters, hepatic function, and renal function did not change significantly. Additional treatment with a longacting calcium antagonist achieved further blood pressure reduction as well as an antihypertrophic effect in the uncontrolled patients with prior ARB monotherapy. (Int Heart J 2009; 50: 555-570)

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“…[34][35][36][37] In vivo, pharmacological blockade of L-type calcium channels effectively suppressed the development of cardiac hypertrophy in spontaneously hypertensive rats through inhibition of calcineurin activity. 38 Several molecules have been identified 36,39 that function as mechanosensors, such as muscle LIM protein within the Z-disc, integrin-linked kinase, and melusin within the costameres (band-like structures linking the sarcolemmal membrane to Z-discs), stretch-sensitive ion channels, G protein-coupled…”

Section: Growth Signals In Physiological Cardiac Hypertrophymentioning

confidence: 99%

Continuous Blockade of L-Type Ca2+ Channels Suppresses Activation of Calcineurin and Development of Cardiac Hypertrophy in Spontaneously Hypertensive Rats

Cited by 43 publications

References 30 publications

The Ca _V 3.2 T-Type Ca ²⁺ Channel Is Required for Pressure Overload–Induced Cardiac Hypertrophy in Mice

The Ca _V 3.2 T-Type Ca ²⁺ Channel Is Required for Pressure Overload–Induced Cardiac Hypertrophy in Mice

Additive Antihypertensive and Antihypertrophic Effects of Long-Acting Ca Blockers in Uncontrolled Hypertensive Patients With Angiotensin-Receptor Blocker Based Treatment

Mechanisms of Cardiovascular Homeostasis and Pathophysiology　– From Gene Expression, Signal Transduction to Cellular Communication –

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Continuous Blockade of L-Type Ca2+ Channels Suppresses Activation of Calcineurin and Development of Cardiac Hypertrophy in Spontaneously Hypertensive Rats

Cited by 43 publications

References 30 publications

The Ca V 3.2 T-Type Ca 2+ Channel Is Required for Pressure Overload–Induced Cardiac Hypertrophy in Mice

The Ca V 3.2 T-Type Ca 2+ Channel Is Required for Pressure Overload–Induced Cardiac Hypertrophy in Mice

Additive Antihypertensive and Antihypertrophic Effects of Long-Acting Ca Blockers in Uncontrolled Hypertensive Patients With Angiotensin-Receptor Blocker Based Treatment

Mechanisms of Cardiovascular Homeostasis and Pathophysiology – From Gene Expression, Signal Transduction to Cellular Communication –

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Product

Resources

About

The Ca _V 3.2 T-Type Ca ²⁺ Channel Is Required for Pressure Overload–Induced Cardiac Hypertrophy in Mice

The Ca _V 3.2 T-Type Ca ²⁺ Channel Is Required for Pressure Overload–Induced Cardiac Hypertrophy in Mice

Mechanisms of Cardiovascular Homeostasis and Pathophysiology　– From Gene Expression, Signal Transduction to Cellular Communication –