A systemic Pasteurella multocida toxin aggravates cardiac hypertrophy and fibrosis in mice
A systemic Pasteurella multocida toxin aggravates cardiac hypertrophy and fibrosis in mice
复制标题
DOI：
10.1111/cmi.12436
复制
发表时间：
2015-09
影响因子：
3.4
通讯作者：
M. Weise;C. Vettel;Katharina Spiger;R. Gilsbach;L. Hein;K. Lorenz;T. Wieland;K. Aktories;Joachim H. C. Orth
中科院分区：
文献类型：
--
作者：
M. Weise;C. Vettel;Katharina Spiger;R. Gilsbach;L. Hein;K. Lorenz;T. Wieland;K. Aktories;Joachim H. C. Orth
多杀性巴氏杆菌毒素可持续激活GαQ/11、Gα12/13和GαI家族的异三聚体G蛋白，而不与G蛋白偶联受体相互作用。我们发现PMT通过异源三聚体G蛋白的脱酰胺作用于体内的心脏组织以及体外的心肌细胞和心脏成纤维细胞。在给予PMT和GPCR激动剂苯肾上腺素联合应用后，检测到正常化的心室重量增加和纤维化。在新生大鼠心肌细胞中，PMT刺激丝裂原活化蛋白激酶通路，这对细胞肥大的发展是至关重要的。毒素诱导了细胞外调节的蛋白1/2的典型磷酸化位点的磷酸化，此外，还引起了最近发现的自磷酸化位点的磷酸化，这似乎在细胞肥大的发展中是重要的。此外，PMT还能刺激小的GTP酶rac1和RhoA。这两种开关蛋白都与心肌细胞肥大有关。此外，PMT还能刺激新生大鼠心脏成纤维细胞的RhoA和rac1。RhoA和rac1参与了结缔组织生长因子(CTGF)的分泌和表达调控。因此，我们发现PMT处理增加了心脏成纤维细胞CTGF的分泌和表达。总之，这些数据表明PMT是心肌细胞病理性重塑的诱导物，并确认该毒素是研究心肌细胞中异三聚体G蛋白依赖的信号转导的一种有前途的工具。
Pasteurella multocida toxin (PMT) persistently activates heterotrimeric G proteins of the Gαq/11, Gα12/13 and Gαi family without interaction with G protein‐coupled receptors (GPCRs). We show that PMT acts on heart tissue in vivo and on cardiomyocytes and cardiac fibroblasts in vitro by deamidation of heterotrimeric G proteins. Increased normalized ventricle weights and fibrosis were detected after intraperitoneal administration of PMT in combination with the GPCR agonist phenylephrine. In neonatal rat cardiomyocytes, PMT stimulated the mitogen‐activated protein kinase pathway, which is crucial for the development of cellular hypertrophy. The toxin induced phosphorylation of the canonical phosphorylation sites of the extracellular‐regulated kinase 1/2 and, additionally, caused phosphorylation of the recently recognized autophosphorylation site, which appears to be important for the development of cellular hypertrophy. Moreover, PMT stimulated the small GTPases Rac1 and RhoA. Both switch proteins are involved in cardiomyocyte hypertrophy. In addition, PMT stimulated RhoA and Rac1 in neonatal rat cardiac fibroblasts. RhoA and Rac1 have been implicated in the regulation of connective tissue growth factor (CTGF) secretion and expression. Accordingly, we show that PMT treatment increased secretion and expression of CTGF in cardiac fibroblasts. Altogether, the data indicate that PMT is an inducer of pathological remodelling of cardiac cells and identifies the toxin as a promising tool for studying heterotrimeric G protein‐dependent signalling in cardiac cells.