丹参酮ⅡA磺酸钠治疗肺动脉高压的作用机制研究
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摘要
【研究背景】:
肺动脉高压(pulmonary arterial hypertension,PAH)是以肺血管壁增厚、重建为主要特征的肺血管疾病,而慢性低氧被认为是引起肺动脉高压的主要因素。慢性低氧性肺动脉高压(CHPH)是大部分慢性阻塞性肺疾病(COPD)患者最终发展成为肺心病而死亡的主要原因。大量的研究证明,细胞内Ca~(2+)在血管平滑肌细胞的收缩和增生的复杂机制中起着至关重要的作用。目前研究发现低氧时SOCC(store-operated calcium channel)上调是引起平滑肌细胞内钙离子失衡的主要原因,SOCC主要由经典瞬时受体电位(canonical transient receptor potential,TRPC)蛋白家族成员组成,慢性低氧能选择性地引起TRPC1、6表达升高。
同时,低氧可以使肺和肺周围血管中的各种促炎因子的表达显著增高,如TNF-α,IL-1β以及IL-6等。这些细胞因子的过度表达对血管壁细胞的表型,包括细胞增殖和基质蛋白的表达,以及对缩血管和舒血管物质反应的改变都起了重要的作用。特别是IL-6,直接参与了COPD以及肺动脉高压的疾病进程。
丹参酮ⅡA磺酸钠(sodium tanshinone IIA sulfonate,STS)是丹参的有效成分丹参酮ⅡA经磺酸化而得到的水溶性产物,最近有研究发现,该药对低氧性肺动脉高压有保护作用,包括降低平均动脉压、能改善右心室肥厚和平滑肌增厚程度,但是其机制尚不清楚。
【研究目的】:
本实验建立了大鼠远端PASMCs (pulmonary arterial smooth muscle cells)原代培养模型及CHPH大鼠模型,观察TRPC通道在CHPH模型及低氧条件下培养的PASMCs中的表达;观察低氧和常氧状态下STS对TRPC1、6表达的影响以及对CHPH大鼠血清中和肺组织中IL-6表达的影响,探讨STS降低CHPH大鼠肺动脉压力的可能机制,为寻找有效的防治肺动脉高压的方法打下坚实的理论基础。
【研究方法】:
本研究采用原代细胞培养和动物实验相结合的方法:(1)胶原酶消化法培养PASMCs:分离正常大鼠远端肺动脉,用胶原酶消化培养大鼠肺动脉平滑肌细胞,通过细胞形态学观察及α-actin免疫荧光染色鉴定平滑肌细胞,应用real-time PCR和Western blot印迹法检测STS对慢性低氧PASMCs的TRPC1、6的mRNA和蛋白的表达,利用InCyte细胞内钙浓度检测系统,分别检测PASMCs的基础[Ca~(2+)]i和SOCE,从而明确STS对慢性低氧大鼠远端PASMCs的[Ca~(2+)]i的影响;(2)建立HPH的动物模型:首先,在慢性持续低氧(10%02)条件下饲养大鼠3周建立CHPH大鼠模型,分别测定右心室收缩压、右心室平均压、右心室肥厚指数;应用real-time PCR和Western blot印迹等分子生物学方法分别检测低氧肺动脉组织TRPC1、6通道mRNA和蛋白表达的变化;用酶联免疫法(ELISA)检测血清中的IL-6的含量;real-time PCR检测肺组织IL-6基因表达。
【实验结果】:
一、体外实验结果:
1、成功建立了大鼠远端PASMCs原代培养模型,原代培养的大鼠远端PASMCs不仅表现出典型的血管平滑肌细胞的形态学和免疫学特征,而且具有完好的生理学功能。
2、慢性低氧使大鼠远端PASMCs的[Ca~(2+)]i和SOCE显著升高,不仅如此,慢性低氧还能使TRPC1、6的mRNA和蛋白表达升高。
3、STS可显著抑制慢性低氧诱导大鼠PASMCs TRPC1、6通道的上调,同时降低基础[Ca~(2+)]i和SOCE。
二、体内实验结果:
l、成功建立CHPH大鼠模型,慢性持续性低氧3周大鼠的MPAP、RVSP、RV/(LV+S)都明显增高,HE染色发现肺动脉血管壁明显增厚、管腔狭窄。
2、CHPH大鼠远端肺动脉平滑肌的TRPC1、6较正常大鼠明显增高。
3、STS可明显降低慢性低氧大鼠mPAP、RVSP、RV/ (LV+S)及肺内血管壁厚度,同时降低慢性低氧大鼠肺动脉组织匀浆中TRPC1、6的表达。
4、慢性肺动脉高压大鼠血清及肺组织中IL-6的表达显著增高,而STS可抑制低氧诱导的IL-6的表达。
【实验结论】:
1、慢性低氧能够上调大鼠远端肺动脉平滑肌细胞中TRPC1、6的表达,增加细胞内钙离子浓度。
2、STS通过抑制低氧对大鼠远端肺动脉平滑肌细胞膜上TRPC1、6通道表达的上调作用,减少SOCC介导的Ca~(2+)内流,从而降低细胞内钙离子浓度。
3、STS能降低慢性低氧大鼠肺动脉组织中TRPC1、6通道表达,这为STS治疗慢性低氧性肺动脉高压提供了理论基础。
4、STS可以改善低氧性肺动脉高压大鼠的心肺病理变化,其机制可能与抑制IL-6的表达有关。
【Background】
Pulmonary arterial hypertension (PAH) is a disease of pulmonary vascular, which is characterized by proliferation and remodeling in the vascular wall. Chronic hypoxia is thought to be an important factor contributing to the development of PAH. Extensively researches showed that intracellular Ca2+ level plays an essential role in the process of distal pulmonary artery constriction and proliferation.What's more, we and other groups have previously found that CH elevated basal [Ca2+]i in PASMCs due in large part to enhanced store-operated Ca2+ entry (SOCE) through store-operated Ca2+ channels (SOCC). SOCC are thought to be composed of canonical transient receptor potential (TRPC) protein family of which TRPC1 and TRPC6 were found to be selectively upregulated by chronic hypoxia in both mRNA and protein level in our previous work.
At the same time, hypoxia can increase expression of various pro- inflammatory cytokines around pulmonary vessel and lung, such as TNF-α、IL-1βand IL-6. Overexpression of these cytokines plays an important role in the phenotype of vascular wall cells, including cell proliferation and matrix protein expression, as well as response to vasoconstrictor and the vasodilator vascular changes. In particular, IL-6 is directly involved in the process of COPD and pulmonary hypertension.
Recent studies showed that sodium tanshinoneⅡA sulfonate (STS), a water-soluble derivative of tanshinoneⅡA which is an active component of Danshen, had protective effects on chronic hypoxic pulmonary hypertension including lowering pulmonary artery pressure (PAP) and decreasing the extent of pulmonary artery thickness and right ventricular hypertrophy. However, the underlying mechanisms remain unclear.
【Objective】
Chronic hypoxic pulmonary hypertension model was established to: measure the expression of TRPC1、6 in PASMCs and pulmonary arteries from CHPH rat; study IL-6 gene expression in lung tissue and IL-6 concentration in blood serum ; estimate the effect of STS on basal [Ca~(2+)]i and SOCE induced by chronic hypoxia in PASMCs and to make sure whether STS has any regulating effect on TRPC1、6 and IL-6, aiming to obtain evidence for further discussion of the CHPH mechanism.
【Methods】
Rat distal PASMCs were isolated and cultured by collagenase digestion and characterized by morphological features and specific immunofluorescenceα-actin staining. Rat distal PASMCs [Ca~(2+)]i were measured using Incyte intracellular Ca~(2+) concentration system. PASMCs were treated by STS of several different concentrations. Both mRNA and protein levels of TRPC1、6 were detected. CHPH rats were obtained using a hypoxic (10%O2) chamber by keeping them in the chamber for 21 days.Animals were treated by STS (10 or 30 mg/kg body weight/day) or equal volume of normal saline intraperitoneal injection before exposed to hypoxia for 3 weeks. Normoxic control animals were put under room air condition and handled accordingly.
Pulmonary hypertension parameters were assessed. Pathological and immunofluorescenceα-actin staining slices were observed under light microscope and fluorescence laser scanning confocal microscope separately. PASMCs were isolated from CHPH rats or normal rats. mRNA and protein levels of TRPC1、6 were detected by real-time PCR and western blot. IL-6 gene expression in lung tissue and IL-6 concentration in blood serum were measured by real-time PCR and ELISA.
【Results】
It was shown that hypoxia increased TRPC1、6 expression in both mRNA and protein levels, triggered Ca~(2+) release from SR and subsequently led to enhanced SOCE in PASMCs. STS inhibited the mRNA and protein upregulation of TRPC1、6 induced by hypoxia in PASMCs. In addition, PASMCs cultured under hypoxic conditions and treated with STS had a weakened response to restoration of extracellular [Ca~(2+)]i。
MPAP、RVSP and RV/(LV+S) were all increased in rats exposed to chronic hypoxia. The pulmonary arteries isolated from CHPH rats were thicker than that from normal rats.On the contrary, the rats under normoxic condition treated with STS were not altered in mPAP、PVSP、RV/(LV+ S) and vascular appearences. Daily application of STS before exposed to hypoxia for 21 days significantly decreased mPAP、PVSP and RV/(LV+ S) compared with those of CHPH rats. Besides, hypoxia increased TRPC1 and TRPC6 mRNA expression in vivo. IL-6 gene expression in lung tissue and IL-6 concentration in blood serum also increased under chronic hypoxia. Treated with STS significantly suppressed these increasing in chronic hypoxic rats.
【Conclusion】
1. Chronic hypoxia increased mRNA and protein expression of TRPC1、6 in PASMCs and increased SOCE.
2. STS has protective inhibiting effects on chronic hypoxia induced increasing in mRNA and protein levels of TRPC1、6 and SOCE in PASMCs.
3. STS has protective inhibiting effects on chronic hypoxia induced increasing in mRNA and protein levels of TRPC1、6 and SOCE in distal pulmonary artery isolated from chronic hypoxic rats.
4. STS inhibited hypoxia-induced increasing of IL-6 gene expression in lung tissue.
5. All the above conclusion indicates that STS may have the potential to become a new effective and possible method for the clinical diagnosis and therapy of CHPH.
肺动脉高压(pulmonary arterial hypertension,PAH)是以肺血管壁增厚、重建为主要特征的肺血管疾病,而慢性低氧被认为是引起肺动脉高压的主要因素。慢性低氧性肺动脉高压(CHPH)是大部分慢性阻塞性肺疾病(COPD)患者最终发展成为肺心病而死亡的主要原因。大量的研究证明,细胞内Ca~(2+)在血管平滑肌细胞的收缩和增生的复杂机制中起着至关重要的作用。目前研究发现低氧时SOCC(store-operated calcium channel)上调是引起平滑肌细胞内钙离子失衡的主要原因,SOCC主要由经典瞬时受体电位(canonical transient receptor potential,TRPC)蛋白家族成员组成,慢性低氧能选择性地引起TRPC1、6表达升高。
同时,低氧可以使肺和肺周围血管中的各种促炎因子的表达显著增高,如TNF-α,IL-1β以及IL-6等。这些细胞因子的过度表达对血管壁细胞的表型,包括细胞增殖和基质蛋白的表达,以及对缩血管和舒血管物质反应的改变都起了重要的作用。特别是IL-6,直接参与了COPD以及肺动脉高压的疾病进程。
丹参酮ⅡA磺酸钠(sodium tanshinone IIA sulfonate,STS)是丹参的有效成分丹参酮ⅡA经磺酸化而得到的水溶性产物,最近有研究发现,该药对低氧性肺动脉高压有保护作用,包括降低平均动脉压、能改善右心室肥厚和平滑肌增厚程度,但是其机制尚不清楚。
【研究目的】:
本实验建立了大鼠远端PASMCs (pulmonary arterial smooth muscle cells)原代培养模型及CHPH大鼠模型,观察TRPC通道在CHPH模型及低氧条件下培养的PASMCs中的表达;观察低氧和常氧状态下STS对TRPC1、6表达的影响以及对CHPH大鼠血清中和肺组织中IL-6表达的影响,探讨STS降低CHPH大鼠肺动脉压力的可能机制,为寻找有效的防治肺动脉高压的方法打下坚实的理论基础。
【研究方法】:
本研究采用原代细胞培养和动物实验相结合的方法:(1)胶原酶消化法培养PASMCs:分离正常大鼠远端肺动脉,用胶原酶消化培养大鼠肺动脉平滑肌细胞,通过细胞形态学观察及α-actin免疫荧光染色鉴定平滑肌细胞,应用real-time PCR和Western blot印迹法检测STS对慢性低氧PASMCs的TRPC1、6的mRNA和蛋白的表达,利用InCyte细胞内钙浓度检测系统,分别检测PASMCs的基础[Ca~(2+)]i和SOCE,从而明确STS对慢性低氧大鼠远端PASMCs的[Ca~(2+)]i的影响;(2)建立HPH的动物模型:首先,在慢性持续低氧(10%02)条件下饲养大鼠3周建立CHPH大鼠模型,分别测定右心室收缩压、右心室平均压、右心室肥厚指数;应用real-time PCR和Western blot印迹等分子生物学方法分别检测低氧肺动脉组织TRPC1、6通道mRNA和蛋白表达的变化;用酶联免疫法(ELISA)检测血清中的IL-6的含量;real-time PCR检测肺组织IL-6基因表达。
【实验结果】:
一、体外实验结果:
1、成功建立了大鼠远端PASMCs原代培养模型,原代培养的大鼠远端PASMCs不仅表现出典型的血管平滑肌细胞的形态学和免疫学特征,而且具有完好的生理学功能。
2、慢性低氧使大鼠远端PASMCs的[Ca~(2+)]i和SOCE显著升高,不仅如此,慢性低氧还能使TRPC1、6的mRNA和蛋白表达升高。
3、STS可显著抑制慢性低氧诱导大鼠PASMCs TRPC1、6通道的上调,同时降低基础[Ca~(2+)]i和SOCE。
二、体内实验结果:
l、成功建立CHPH大鼠模型,慢性持续性低氧3周大鼠的MPAP、RVSP、RV/(LV+S)都明显增高,HE染色发现肺动脉血管壁明显增厚、管腔狭窄。
2、CHPH大鼠远端肺动脉平滑肌的TRPC1、6较正常大鼠明显增高。
3、STS可明显降低慢性低氧大鼠mPAP、RVSP、RV/ (LV+S)及肺内血管壁厚度,同时降低慢性低氧大鼠肺动脉组织匀浆中TRPC1、6的表达。
4、慢性肺动脉高压大鼠血清及肺组织中IL-6的表达显著增高,而STS可抑制低氧诱导的IL-6的表达。
【实验结论】:
1、慢性低氧能够上调大鼠远端肺动脉平滑肌细胞中TRPC1、6的表达,增加细胞内钙离子浓度。
2、STS通过抑制低氧对大鼠远端肺动脉平滑肌细胞膜上TRPC1、6通道表达的上调作用,减少SOCC介导的Ca~(2+)内流,从而降低细胞内钙离子浓度。
3、STS能降低慢性低氧大鼠肺动脉组织中TRPC1、6通道表达,这为STS治疗慢性低氧性肺动脉高压提供了理论基础。
4、STS可以改善低氧性肺动脉高压大鼠的心肺病理变化,其机制可能与抑制IL-6的表达有关。
【Background】
Pulmonary arterial hypertension (PAH) is a disease of pulmonary vascular, which is characterized by proliferation and remodeling in the vascular wall. Chronic hypoxia is thought to be an important factor contributing to the development of PAH. Extensively researches showed that intracellular Ca2+ level plays an essential role in the process of distal pulmonary artery constriction and proliferation.What's more, we and other groups have previously found that CH elevated basal [Ca2+]i in PASMCs due in large part to enhanced store-operated Ca2+ entry (SOCE) through store-operated Ca2+ channels (SOCC). SOCC are thought to be composed of canonical transient receptor potential (TRPC) protein family of which TRPC1 and TRPC6 were found to be selectively upregulated by chronic hypoxia in both mRNA and protein level in our previous work.
At the same time, hypoxia can increase expression of various pro- inflammatory cytokines around pulmonary vessel and lung, such as TNF-α、IL-1βand IL-6. Overexpression of these cytokines plays an important role in the phenotype of vascular wall cells, including cell proliferation and matrix protein expression, as well as response to vasoconstrictor and the vasodilator vascular changes. In particular, IL-6 is directly involved in the process of COPD and pulmonary hypertension.
Recent studies showed that sodium tanshinoneⅡA sulfonate (STS), a water-soluble derivative of tanshinoneⅡA which is an active component of Danshen, had protective effects on chronic hypoxic pulmonary hypertension including lowering pulmonary artery pressure (PAP) and decreasing the extent of pulmonary artery thickness and right ventricular hypertrophy. However, the underlying mechanisms remain unclear.
【Objective】
Chronic hypoxic pulmonary hypertension model was established to: measure the expression of TRPC1、6 in PASMCs and pulmonary arteries from CHPH rat; study IL-6 gene expression in lung tissue and IL-6 concentration in blood serum ; estimate the effect of STS on basal [Ca~(2+)]i and SOCE induced by chronic hypoxia in PASMCs and to make sure whether STS has any regulating effect on TRPC1、6 and IL-6, aiming to obtain evidence for further discussion of the CHPH mechanism.
【Methods】
Rat distal PASMCs were isolated and cultured by collagenase digestion and characterized by morphological features and specific immunofluorescenceα-actin staining. Rat distal PASMCs [Ca~(2+)]i were measured using Incyte intracellular Ca~(2+) concentration system. PASMCs were treated by STS of several different concentrations. Both mRNA and protein levels of TRPC1、6 were detected. CHPH rats were obtained using a hypoxic (10%O2) chamber by keeping them in the chamber for 21 days.Animals were treated by STS (10 or 30 mg/kg body weight/day) or equal volume of normal saline intraperitoneal injection before exposed to hypoxia for 3 weeks. Normoxic control animals were put under room air condition and handled accordingly.
Pulmonary hypertension parameters were assessed. Pathological and immunofluorescenceα-actin staining slices were observed under light microscope and fluorescence laser scanning confocal microscope separately. PASMCs were isolated from CHPH rats or normal rats. mRNA and protein levels of TRPC1、6 were detected by real-time PCR and western blot. IL-6 gene expression in lung tissue and IL-6 concentration in blood serum were measured by real-time PCR and ELISA.
【Results】
It was shown that hypoxia increased TRPC1、6 expression in both mRNA and protein levels, triggered Ca~(2+) release from SR and subsequently led to enhanced SOCE in PASMCs. STS inhibited the mRNA and protein upregulation of TRPC1、6 induced by hypoxia in PASMCs. In addition, PASMCs cultured under hypoxic conditions and treated with STS had a weakened response to restoration of extracellular [Ca~(2+)]i。
MPAP、RVSP and RV/(LV+S) were all increased in rats exposed to chronic hypoxia. The pulmonary arteries isolated from CHPH rats were thicker than that from normal rats.On the contrary, the rats under normoxic condition treated with STS were not altered in mPAP、PVSP、RV/(LV+ S) and vascular appearences. Daily application of STS before exposed to hypoxia for 21 days significantly decreased mPAP、PVSP and RV/(LV+ S) compared with those of CHPH rats. Besides, hypoxia increased TRPC1 and TRPC6 mRNA expression in vivo. IL-6 gene expression in lung tissue and IL-6 concentration in blood serum also increased under chronic hypoxia. Treated with STS significantly suppressed these increasing in chronic hypoxic rats.
【Conclusion】
1. Chronic hypoxia increased mRNA and protein expression of TRPC1、6 in PASMCs and increased SOCE.
2. STS has protective inhibiting effects on chronic hypoxia induced increasing in mRNA and protein levels of TRPC1、6 and SOCE in PASMCs.
3. STS has protective inhibiting effects on chronic hypoxia induced increasing in mRNA and protein levels of TRPC1、6 and SOCE in distal pulmonary artery isolated from chronic hypoxic rats.
4. STS inhibited hypoxia-induced increasing of IL-6 gene expression in lung tissue.
5. All the above conclusion indicates that STS may have the potential to become a new effective and possible method for the clinical diagnosis and therapy of CHPH.
引文
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