肝细胞生长因子抗压力负荷性心肌肥厚作用及机制

Pressure overload cardiac hypertrophy is common complication in hypertension. ACEI and calcium channel blockers are the main curative drugs in hypertrophy therapy with high costs. The researchers have focused to new anti-hypertrophy drugs with high efficacy and low toxicity and relative cheaper price. Hepatocyte growth factor (HGF) has been identified as a primary candidate in promoting and regulating liver regeneration, and was later reported to have mitogenic, motogenic, morphogenic, and anti-apoptotic activities in various cell types. By promoting angiogenesis and inhibiting fibrosis, HGF may play an important role in cardioprotection after myocardial infarction. HGF potently stimulates angiogenesis and prevents cardiac hypertrophy and fibosis in chronic heart failure. It is still unknown whether HGF may work in pressure overload cardiac hypertrophy. In this study, our aim is to evaluate the therapeutic value of HGF in pressure overload cardiac hypertrophy. The models include partial coarctation in the abdominal aorta in rats and phenylephrine (PE) induced primary cardiomyocytes hypertrophy of neonatal rats and PE induced myocytes hypertrophy in H9c2 cell line. The methods include Laser scanning confocal microscope technique, patch clamp technique, flow cytometer technique and Western Blot technique. We hypothesized that HGF may prevent pressure overload cardiac hypertrophy and inhibiting [Ca2+]i-calcineurin signal pathway may be involved in the action. This study could reveal a new protective mechanism of HGF, offer a new drug for hypertrophy, and find a new usage of HGF in clinic.

压力负荷性心肌肥厚是高血压等心脏病最常见的并发症，目前治疗药物主要是ACEI和钙通道阻滞剂，其费用相对昂贵，故寻找高效低毒、经济合理的抗心肌肥厚药物一直是国内外研究热点。肝细胞生长因子（HGF）是间质细胞衍生的一种促细胞有丝分裂的多功能因子，目前临床主要用于促进肝细胞再生和抗组织纤维化。近年发现HGF也是一种心肌保护因子，在心肌梗死等多种心血管疾病中起重要保护作用，但其是否具有抗压力负荷性心肌肥厚作用尚未见报道。本课题主要应用共聚焦、膜片钳、流式细胞、Western Blot等技术在腹主动脉部分缩窄所致大鼠心肌肥厚模型和去氧肾上腺素诱导乳鼠原代心肌细胞及H9c2细胞肥大模型上验证HGF是否具有抑制心肌细胞肥大的作用，并探讨其内在机制是否通过"钙通道、细胞内钙和钙调神经磷酸酶-NFAT信号途径"起作用。本研究可揭示HGF作用的新机制，为心肌肥厚治疗提供新药物，还可为HGF提供临床新用途。

心肌肥厚是高血压等心脏病最常见的并发症，寻找高效低毒、经济合理的抗心肌肥厚药物始终是国内外研究热点。肝细胞生长因子（HGF）是间质细胞衍生的一种促细胞有丝分裂的多功能因子，近年来其心血管保护作用备受关注，但其是否具有抗压力负荷性心肌肥厚作用尚未见报道。.本课题主要建立了小鼠腹主动脉部分缩窄所致心肌肥厚模型和去氧肾上腺素诱导乳鼠原代心肌细胞及H9c2细胞肥大模型，用小动物超声心动检测心功，无创血压检测技术监控血压变化，HE和Masson染色进行心肌形态学检查，用western blot技术检测钙调神经磷酸激酶表达，激光扫描共聚焦技术检测心肌细胞内钙浓度，膜片钳技术进行心肌细胞离子通道功能检测等，用以验证肝细胞生长因子（HGF）是否具有抑制心肌细胞肥大的作用，并探讨其内在机制。.成功建立了小鼠腹主动脉部分缩窄所致心肌肥厚模型和去氧肾上腺素诱导乳鼠原代心肌细胞及H9c2细胞肥大模型。结果显示HGF可以改善心肌肥厚模型的心功、逆转压力负荷所致的心肌重构、减少心肌胶原生成；HGF可以抑制乳鼠原代心肌细胞和H9c2细胞的肥大，减少钙调神经磷酸激酶的表达，降低细胞内钙浓度；HGF可以降低急性分离大鼠心肌细胞内钙浓度，既抑制肌浆网钙库释放，也抑制外钙内流。.本实验从病理模型、功能学、蛋白表达等方面证明HGF可以抑制心肌肥厚，其内在机制与抑制“钙通道、细胞内钙和钙调神经磷酸酶-NFAT信号途径”相关。该作用是HGF的临床新用途，具有较大的经济和社会效益。