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Apela基因疗法减轻大鼠肺动脉高压

2022-06-27 刘少飞 MedSci原创

肺动脉高压Apela
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最近，apelin 空肠肽(APJ)受体的新型内源性配体Apela被鉴定为可能的 PAH 靶标。本研究探讨了Apela 基因治疗对 PAH大鼠的潜在影响。

肺动脉高压(PAH)是由多种原因引起的肺动脉压异常升高的病理生理状态。PAH是一种破坏性疾病，主要局限于肺小动脉，以肺血管阻力增加和右心衰竭为特征。右心衰竭是肺动脉高压最常见的死亡原因。PAH 的病因尚不完全清楚。目前用于治疗肺动脉高压的药物有内皮素-1（ET-1）受体拮抗剂、前列环素类似物和磷酸二酯酶5抑制剂。这些治疗剂的主要作用是维持内皮源性血管活性介质的平衡和扩张肺血管，以治疗PAH。PAH是一种严重威胁人类健康的常见病。但至今仍无根治，预后差，病死率高。因此，确定 PAH 治疗的新靶点很重要。

最近的研究发现，Apela，又名 ELABELA/Toddler/ELA32，是 apelin 空肠肽 (APJ) 受体的新配体，不仅在心脏发育、心力衰竭、维持体液平衡和血管生成中发挥重要的生物学作用，而且在肺动脉大鼠模型中，在降低肺动脉高压和改善右心功能衰竭方面也具有重要的生物学作用。以前的研究表明基因治疗对肺动脉高压有成功的效果。本研究进一步探讨了腺相关病毒 (AAV) 介导的 Apela 基因治疗在大鼠肺动脉高压模型中的生物学效应和潜在分子机制。

通过分子克隆构建了AAV-ELA32重组表达载体。在建模后 1 周和 2 周，通过尾静脉将纯化的腺相关病毒 (AAV) 注射到野百合碱 (MCT) 诱导的 PAH 大鼠中。

Apela 基因治疗显着降低了 PAH 大鼠增加的右心室收缩压和 N 端脑利钠肽前体 (NT-proBNP)。组织病理学和免疫荧光结果表明，Apela基因治疗不仅降低了PAH大鼠肺小动脉肌化和中膜增厚的速度，而且抑制了肺小动脉的内皮-间质转化。Western印迹显示Apela基因治疗上调PAH大鼠肺小动脉中KLF2/eNOs和BMPRII/SMAD4的表达。总体而言，结果表明Apela基因治疗可以抑制PAH大鼠肺小动脉血管重构，降低肺动脉压。这些影响可能与 KLF2/eNOs 和 BMPRII/SMAD4 信号通路有关。apelinergic系统可能是预防和治疗PAH的潜在新靶点。

 

参考文献：

Hu Y, Jin L, Pan Y, Zou J, Wang Z. Apela gene therapy alleviates pulmonary hypertension in rats. FASEB J. 2022 Jul;36(7):e22431. doi: 10.1096/fj.202200266R. PMID: 35747913.

 

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    2023-02-28 jklm09

    #动脉高压#

    0

  2. [GetPortalCommentsPageByObjectIdResponse(id=1925618, encodeId=4d3f19256185e, content=<a href='/topic/show?id=26d633354c9' target=_blank style='color:#2F92EE;'>#动脉高压#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=46, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=33354, encryptionId=26d633354c9, topicName=动脉高压)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Tue Feb 28 13:41:50 CST 2023, time=2023-02-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1239906, encodeId=1190123990634, content=<a href='/topic/show?id=567041e8055' target=_blank style='color:#2F92EE;'>#基因治疗#</a><a href='/topic/show?id=0bad820e112' target=_blank style='color:#2F92EE;'>#肺动脉高压#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=1, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=41780, encryptionId=567041e8055, topicName=基因治疗), TopicDto(id=82071, encryptionId=0bad820e112, topicName=肺动脉高压)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/Random/55971dc507c93968175ce7cc1e177b372a83869f.jpg, createdBy=f63e4754896, createdName=小小医者, createdTime=Sat Aug 20 07:07:02 CST 2022, time=2022-08-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1729642, encodeId=45e51e2964245, content=<a href='/topic/show?id=986913980dd' target=_blank style='color:#2F92EE;'>#PE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13980, encryptionId=986913980dd, topicName=PE)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f06c33759375, createdName=feather89, createdTime=Sun Sep 04 01:41:50 CST 2022, time=2022-09-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1625855, encodeId=8c1316258555e, content=<a href='/topic/show?id=bc29140196e' target=_blank style='color:#2F92EE;'>#PEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=14019, encryptionId=bc29140196e, topicName=PEL)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=399320916411, createdName=tidiq, createdTime=Tue Jun 28 07:41:50 CST 2022, time=2022-06-28, status=1, ipAttribution=)]
    2022-08-20 小小医者

    #基因治疗##肺动脉高压#

    0

  3. [GetPortalCommentsPageByObjectIdResponse(id=1925618, encodeId=4d3f19256185e, content=<a href='/topic/show?id=26d633354c9' target=_blank style='color:#2F92EE;'>#动脉高压#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=46, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=33354, encryptionId=26d633354c9, topicName=动脉高压)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Tue Feb 28 13:41:50 CST 2023, time=2023-02-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1239906, encodeId=1190123990634, content=<a href='/topic/show?id=567041e8055' target=_blank style='color:#2F92EE;'>#基因治疗#</a><a href='/topic/show?id=0bad820e112' target=_blank style='color:#2F92EE;'>#肺动脉高压#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=1, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=41780, encryptionId=567041e8055, topicName=基因治疗), TopicDto(id=82071, encryptionId=0bad820e112, topicName=肺动脉高压)], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/Random/55971dc507c93968175ce7cc1e177b372a83869f.jpg, createdBy=f63e4754896, createdName=小小医者, createdTime=Sat Aug 20 07:07:02 CST 2022, time=2022-08-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1729642, encodeId=45e51e2964245, content=<a href='/topic/show?id=986913980dd' target=_blank style='color:#2F92EE;'>#PE#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13980, encryptionId=986913980dd, topicName=PE)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f06c33759375, createdName=feather89, createdTime=Sun Sep 04 01:41:50 CST 2022, time=2022-09-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1625855, encodeId=8c1316258555e, content=<a href='/topic/show?id=bc29140196e' target=_blank style='color:#2F92EE;'>#PEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=14019, encryptionId=bc29140196e, topicName=PEL)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=399320916411, createdName=tidiq, createdTime=Tue Jun 28 07:41:50 CST 2022, time=2022-06-28, status=1, ipAttribution=)]
    2022-09-04 feather89

    #PE#

    0

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    2022-06-28 tidiq

    #PEL#

    0

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