Transient receptor potential channels contribute to pathological structural and functional remodeling after myocardial infarction.
Transient receptor potential channels contribute to pathological structural and functional remodeling after myocardial infarction.
复制标题
DOI：
10.1161/circresaha.115.303831
复制
发表时间：
2014-08-29
影响因子：
20.1
通讯作者：
Houser SR
中科院分区：
文献类型：
--
作者：
Makarewich CA;Zhang H;Davis J;Correll RN;Trappanese DM;Hoffman NE;Troupes CD;Berretta RM;Kubo H;Madesh M;Chen X;Gao E;Molkentin JD;Houser SR
心肌梗死（MI）后结构和功能重构的细胞和分子基础尚不清楚。确定通过瞬时受体电位（经典）（TRPC）通道的Ca 2+内流是否有助于MI后结构和功能重塑。心肌梗死后TRPC 1/3/4/6通道mRNA表达增加，与TRPC介导的Ca ~（2+）内流有关。心肌细胞特异性表达显性负性（dn：功能丧失）TRPC 4通道增加了心肌细胞的基础收缩力，减少了心肌梗死后的肥大和心脏结构和功能重塑，同时增加了存活率。我们使用腺病毒介导的TRPC 3/4/6通道在培养的成年猫肌细胞（AFM）的表达，以确定这些TRPC相关的影响的机制方面。TRPC 3/4/6在AFM中的过表达诱导钙调神经磷酸酶（Cn）-活化T细胞核因子（NFAT）介导的肥大信号传导，这依赖于TRPC的小窝靶向。TRPC 3/4/6在AFM中的表达增加静息状态收缩，并增加由ryanodine受体的磷酸化增强介导的自发肌浆网（SR）Ca 2+火花。TRPC 3/4/6表达与稳态起搏期间收缩性降低和对儿茶酚胺的反应相关，可能是由于增强的SR Ca 2+泄漏。心肌梗死后通过TRPC通道表达的Ca 2+内流激活病理性心肌肥大并降低收缩力储备。阻断MI后TRPC活性可改善MI后心脏结构和功能。
The cellular and molecular basis for post myocardial infarction (MI) structural and functional remodeling is not well understood. To determine if Ca2+ influx through transient receptor potential (canonical) (TRPC) channels contributes to post-MI structural and functional remodeling. TRPC1/3/4/6 channel mRNA increased after MI in mice and was associated with TRPC-mediated Ca2+ entry. Cardiac myocyte specific expression of a dominant negative (dn: loss of function) TRPC4 channel increased basal myocyte contractility and reduced hypertrophy and cardiac structural and functional remodeling after MI while increasing survival. We used adenovirus-mediated expression of TRPC3/4/6 channels in cultured adult feline myocytes (AFMs) to define mechanistic aspects of these TRPC-related effects. TRPC3/4/6 over expression in AFMs induced calcineurin (Cn)-Nuclear Factor of Activated T cells (NFAT) mediated hypertrophic signaling, which was reliant on caveolae targeting of TRPCs. TRPC3/4/6 expression in AFMs increased rested state contractions and increased spontaneous sarcoplasmic reticulum (SR) Ca2+ sparks mediated by enhanced phosphorylation of the ryanodine receptor. TRPC3/4/6 expression was associated with reduced contractility and response to catecholamines during steady state pacing, likely due to enhanced SR Ca2+ leak. Ca2+ influx through TRPC channels expressed after MI activates pathological cardiac hypertrophy and reduces contractility reserve. Blocking post-MI TRPC activity improved post-MI cardiac structure and function.