Age attenuates the T-type CaV 3.2-RyR axis in vascular smooth muscle.,Aging Cell

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Age attenuates the T-type CaV 3.2-RyR axis in vascular smooth muscle.
Aging Cell ( IF 8.0 ) Pub Date : 2020-03-18 , DOI: 10.1111/acel.13134
Gang Fan _{1,

2} , Mario Kaßmann ₁ , Yingqiu Cui ₁ , Claudia Matthaeus ₃ , Séverine Kunz ₄ , Cheng Zhong ₁ , Shuai Zhu ₂ , Yu Xie ₂ , Dmitry Tsvetkov ₁ , Oliver Daumke _{3,

5} , Yu Huang ₆ , Maik Gollasch _{1,

7,

8}

Affiliation

Caveolae position Ca_V3.2 (T‐type Ca²⁺ channel encoded by the α‐3.2 subunit) sufficiently close to RyR (ryanodine receptors) for extracellular Ca²⁺ influx to trigger Ca²⁺ sparks and large‐conductance Ca²⁺‐activated K⁺ channel feedback in vascular smooth muscle. We hypothesize that this mechanism of Ca²⁺ spark generation is affected by age. Using smooth muscle cells (VSMCs) from mouse mesenteric arteries, we found that both Ca_v3.2 channel inhibition by Ni²⁺ (50 µM) and caveolae disruption by methyl‐ß‐cyclodextrin or genetic abolition of Eps15 homology domain‐containing protein (EHD2) inhibited Ca²⁺ sparks in cells from young (4 months) but not old (12 months) mice. In accordance, expression of Ca_v3.2 channel was higher in mesenteric arteries from young than old mice. Similar effects were observed for caveolae density. Using SMAKO Ca_v1.2^−/− mice, caffeine (RyR activator) and thapsigargin (Ca²⁺ transport ATPase inhibitor), we found that sufficient SR Ca²⁺ load is a prerequisite for the Ca_V3.2‐RyR axis to generate Ca²⁺ sparks. We identified a fraction of Ca²⁺ sparks in aged VSMCs, which is sensitive to the TRP channel blocker Gd³⁺ (100 µM), but insensitive to Ca_V1.2 and Ca_V3.2 channel blockade. Our data demonstrate that the VSMC Ca_V3.2‐RyR axis is down‐regulated by aging. This defective Ca_V3.2‐RyR coupling is counterbalanced by a Gd³⁺ sensitive Ca²⁺ pathway providing compensatory Ca²⁺ influx for triggering Ca²⁺ sparks in aged VSMCs.

中文翻译：

年龄减弱了血管平滑肌的T型CaV 3.2-RyR轴。

小窝位置Ca _V 3.2（由α-3.2亚基编码的T型Ca ²⁺通道）足够接近RyR（ryanodine受体），可引起细胞外Ca ²⁺大量涌入，触发Ca ²⁺火花和大电导Ca ²⁺激活血管平滑肌中的K ⁺通道反馈。我们假设Ca ²⁺火花生成的这种机制受年龄的影响。使用来自小鼠肠系膜动脉的平滑肌细胞（VSMC），我们发现Ni ²⁺（50 µM）对Ca _v 3.2通道的抑制和甲基ß-环糊精对海绵体的破坏或对含Eps15同源域蛋白（EHD2）的遗传废除）抑制钙幼鼠（4个月）而不是老年鼠（12个月）的细胞中产生^2+种火花。因此，年轻小鼠的肠系膜动脉中Ca _v 3.2通道的表达高于老年小鼠。对于小窝密度观察到类似的效果。使用SMAKO Ca _v 1.2 ^-/-小鼠，咖啡因（RyR激活剂）和毒胡萝卜素（Ca ²⁺转运ATPase抑制剂），我们发现足够的SR Ca ²⁺负载是Ca _V 3.2-RyR轴生成Ca ²的先决条件⁺火花。我们在老化的VSMC中确定了一部分Ca ²⁺火花，该火花对TRP通道阻滞剂Gd ³⁺（100 µM）敏感，但对Ca _V不敏感1.2和Ca _V 3.2通道封锁。我们的数据表明，VSMC Ca _V 3.2-RyR轴会因老化而下调。这种有缺陷的Ca _V 3.2-RyR耦合通过Gd ³⁺敏感的Ca ²⁺途径抵消，该途径提供补偿性Ca ²⁺流入，以触发老化的VSMC中的Ca ²⁺火花。

更新日期：2020-03-18

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