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PNAS:sEH抑制剂能阻断心肌纤维化

2013-04-04 生物通 生物通

心脏病发作后的组织损伤往往会最终导致心力衰竭,而加州大学Davis分校(UC Davis)的一项新研究,通过抑制一个促炎症的酶阻断了上述组织损伤,此外研究人员还确定了其中的分子机制。文章发表在美国国家科学院院刊PNAS杂志上。 可溶性环氧化物水解酶sEH,是组织修复相关免疫应答中的关键成员,不过在心脏病发作后,这种酶往往会产生事与愿违的影响。Chiamvimonvat解释道,sEH使促炎症的脂类

心脏病发作后的组织损伤往往会最终导致心力衰竭,而加州大学Davis分校(UC Davis)的一项新研究,通过抑制一个促炎症的酶阻断了上述组织损伤,此外研究人员还确定了其中的分子机制。文章发表在美国国家科学院院刊PNAS杂志上。

可溶性环氧化物水解酶sEH,是组织修复相关免疫应答中的关键成员,不过在心脏病发作后,这种酶往往会产生事与愿违的影响。Chiamvimonvat解释道,sEH使促炎症的脂类介质增多,从而引起高水平的炎症,另外这种酶还会引发疤痕组织或者纤维化,最终使心脏功能衰退。研究人员在Nipavan Chiamvimonvat教授的带领下,对sEH抑制剂进行了测试。

“在临床上常常出现这样的现象,心脏病发作的患者一开始治疗效果良好,”致力于研究心脏病生物学机制的Chiamvimonvat说。“但随着时间推移,一些患者的心脏功能持续恶化,导致心力衰竭。”

心力衰竭会逐渐限制全身的氧供给,损害患者的运动能力、呼吸能力和生活质量。据美国疾控中心统计,这种疾病影响了五百七十万美国人,造成了大量的经济损失。约有半数的心力衰竭患者在确诊后的五年内死亡。.

此前,研究人员曾发现sEH抑制剂能够缓解心肌细胞增大和相应心律失常。现在他们又进行了一系列实验,测试这一化合物治疗心肌纤维化的能力。心脏病发作和慢性心脏疾病都有可能引起心肌纤维化,因此研究人员对心脏病发作和高血压小鼠模型分别进行了研究。高血压会给心脏带来慢性的压力负荷。

研究人员将上述小鼠模型各分为两组,一组通过饮用水摄入sEH抑制剂,一组作为对照。然后他们通过超声心动图echocardiography来评价这些小鼠的心脏功能。研究显示,sEH抑制剂显著减少了小鼠体内的有害心肌重塑,使其总体心脏功能得到改善。有害心脏重塑包括心肌细胞肥大、纤维化和电重构。

“心脏纤维化是心脏病学中最棘手的问题之一,而我们为此提供了新的治疗靶标,”文章的共同作者,助理教授Javier Lopez说。研究人员指出,接受抑制剂治疗的小鼠,体内的炎症因子也显著减少。

下一步,研究团队希望在更大型的模式动物中测试sEH抑制剂的治疗效果,然后进入人类临床试验。该研究的作者中还包括山东大学的赵翠芬(音译Cuifen Zhao)

doi:10.1073/pnas.1221972110
PMC:
PMID:

Unique mechanistic insights into the beneficial effects of soluble epoxide hydrolase inhibitors in the prevention of cardiac fibrosis

Sirish P, Li N, Liu JY, Lee KS, Hwang SH, Qiu H, Zhao C, Ma SM, López JE, Hammock BD, Chiamvimonvat N.

Tissue fibrosis represents one of the largest groups of diseases for which there are very few effective therapies. In the heart, myocardial infarction (MI) resulting in the loss of cardiac myocytes can culminate in adverse cardiac remodeling leading to eventual heart failure. Adverse cardiac remodeling includes myocyte hypertrophy, fibrosis, and electrical remodeling. We have previously demonstrated the beneficial effects of several potent soluble epoxide hydrolase inhibitors (sEHIs) in different models of cardiac hypertrophy and failure. Here, we directly determine the molecular mechanisms underlying the beneficial effects of sEHIs in cardiac remodeling post-MI. Treatment with a potent sEHI, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU), which was started 1 wk post-MI in a murine model, results in a significant improvement in cardiac function. Importantly, treatment with TPPU results in a decrease in cardiac fibrosis as quantified using histological and immunostaining techniques. Moreover, single-cell-based assays demonstrate that treatment with TPPU results in a significant decrease not only in the percentages but also the proliferative capacity of different populations of cardiac fibroblasts as well as a reduction in the migration of fibroblasts into the heart from the bone marrow. Our study provides evidence for a possible unique therapeutic strategy to reduce cardiac fibrosis and improve cardiac function post-MI .

 

(责任编辑:lili.zhao)

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    2013-12-10 drwjr
  2. [GetPortalCommentsPageByObjectIdResponse(id=1855375, encodeId=a00318553e528, content=<a href='/topic/show?id=f32014428fc' target=_blank style='color:#2F92EE;'>#PNAS#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=55, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=14428, encryptionId=f32014428fc, topicName=PNAS)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=08e964, createdName=drwjr, createdTime=Tue Dec 10 14:03:00 CST 2013, time=2013-12-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1851114, encodeId=b9481851114ad, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Tue Jun 25 05:03:00 CST 2013, time=2013-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2078003, encodeId=02d920e8003bc, content=<a href='/topic/show?id=8a8580960a5' target=_blank style='color:#2F92EE;'>#肌纤维#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=76, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=80960, encryptionId=8a8580960a5, topicName=肌纤维)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ea6321, createdName=okhuali, createdTime=Sat Jan 11 13:03:00 CST 2014, time=2014-01-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1709971, encodeId=f4c91e0997198, content=<a href='/topic/show?id=7ac59e67604' target=_blank style='color:#2F92EE;'>#阻断#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=94, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97676, encryptionId=7ac59e67604, topicName=阻断)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b5ca31824852, createdName=41514497@qq.com, createdTime=Sun Sep 08 10:03:00 CST 2013, time=2013-09-08, status=1, ipAttribution=)]
    2013-06-25 jklm09
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    2014-01-11 okhuali
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