Differential cardiac remodeling in preload versus afterload.
Differential cardiac remodeling in preload versus afterload.
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DOI：
10.1161/circulationaha.110.943431
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发表时间：
2010-09-07
期刊：
影响因子：
37.8
通讯作者：
Hasenfuss G
中科院分区：
文献类型：
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作者：
Toischer K;Rokita AG;Unsöld B;Zhu W;Kararigas G;Sossalla S;Reuter SP;Becker A;Teucher N;Seidler T;Grebe C;Preuss L;Gupta SN;Schmidt K;Lehnart SE;Krüger M;Linke WA;Backs J;Regitz-Zagrosek V;Schäfer K;Field LJ;Maier LS;Hasenfuss G
血流动力学负荷调节心肌功能和基因表达。我们检验了后负荷和前负荷尽管平均负荷相似但表型不同的假设。在横向主动脉缩窄（TAC）和腹主动脉-腔静脉分流（Shunt）小鼠中比较后负荷和前负荷。与假手术小鼠相比，手术后6小时，（后负荷）增加，（+40%，P <0.05），分流组舒张期室壁应力（前负荷）增加TAC（+277%，P<0.05）和TAC（+74%，P<0.05）中的平均总壁应力相似地增加（69%）和分流（67%）（TAC与分流：不显著（n.s.），每种P<0.05相对于假手术）。在1周时，左心室重量/胫骨长度在TAC中显著增加22%，在分流中显著增加29%（n.s. TAC与分流术）。在24小时和1周后，TAC中的钙/钙调蛋白依赖性蛋白激酶II（CaMKII）信号传导增加。这导致钙循环改变，包括L型钙电流、钙瞬变、部分SR释放和钙火花频率增加。在分流中，Akt磷酸化增加。TAC与炎症、纤维化和心肌细胞凋亡有关。后者在CaMKIIδ-KO TAC小鼠中显著降低。在TAC与分流中，157种mRNA和13种microRNA差异调节。8周后，TAC后负荷导致适应不良的纤维化肥大伴CaMKII依赖性钙循环改变和细胞凋亡，缩短分数较低，死亡率较高。前负荷与Akt激活相关，无纤维化，凋亡少，功能更好，死亡率更低。这表明，不同的负荷导致不同的表型差异，这可能需要特定的药理学干预。
Hemodynamic load regulates myocardial function and gene expression. We tested the hypothesis that afterload and preload despite similar average load result in different phenotypes. Afterload and preload were compared in mice with transversal aortic constriction (TAC) and aorto-caval shunt (Shunt). When compared to sham mice, six hours after surgery, systolic wall stress (afterload) was increased in TAC (+40%, P<0.05), diastolic wall stress (preload) was increased in Shunt (+277%, P<0.05) and TAC (+74%, P<0.05) and mean total wall stress was similarly increased in TAC (69%) and Shunt (67%) (TAC vs. Shunt: not significant (n.s.), each P<0.05 vs. Sham). At 1 week, left ventricular weight/tibia length was significantly increased by 22% in TAC and 29% in Shunt (n.s. TAC vs. Shunt). After 24 hours and 1 week, calcium/calmodulin dependent protein kinase II (CaMKII) signaling was increased in TAC. This resulted in altered calcium cycling, including increased L-type calcium current, calcium transients, fractional SR release and calcium spark frequency. In Shunt, Akt phosphorylation was increased. TAC was associated with inflammation, fibrosis and cardiomyocyte apoptosis. The latter was significantly reduced in CaMKIIδ-KO TAC mice. 157 mRNAs and 13 microRNAs were differentially regulated in TAC vs. Shunt. After 8 weeks, fractional shortening was lower and mortality higher in TAC Afterload results in maladaptive fibrotic hypertrophy with CaMKII-dependent altered calcium cycling and apoptosis. Preload is associated with Akt activation without fibrosis, little apoptosis, better function and lower mortality. This indicates that different loads result in distinct phenotype differences which may require specific pharmacological interventions.