β3-Adrenergic receptor overexpression in cardiomyocytes preconditions mitochondria to withstand ischemia-reperfusion injury.

IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Basic Research in Cardiology Pub Date : 2024-10-01 Epub Date: 2024-08-12 DOI:10.1007/s00395-024-01072-y
Miguel Fernández-Tocino, Andrés Pun-Garcia, Mónica Gómez, Agustín Clemente-Moragón, Eduardo Oliver, Rocío Villena-Gutierrez, Sofía Trigo-Anca, Anabel Díaz-Guerra, David Sanz-Rosa, Belén Prados, Lara Del Campo, Vicente Andrés, Valentín Fuster, José Luis de la Pompa, Laura Cádiz, Borja Ibañez
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Abstract

β3-Adrenergic receptor (β3AR) agonists have been shown to protect against ischemia-reperfusion injury (IRI). Since β3ARs are present both in cardiomyocytes and in endothelial cells, the cellular compartment responsible for this protection has remained unknown. Using transgenic mice constitutively expressing the human β3AR (hβ3AR) in cardiomyocytes or in the endothelium on a genetic background of null endogenous β3AR expression, we show that only cardiomyocyte expression protects against IRI (45 min ischemia followed by reperfusion over 24 h). Infarct size was also limited after ischemia-reperfusion in mice with cardiomyocyte hβ3AR overexpression on top of endogenous β3AR expression. hβ3AR overexpression in these mice reduced IRI-induced cardiac fibrosis and improved long-term left ventricular systolic function. Cardiomyocyte-specific β3AR overexpression resulted in a baseline remodeling of the mitochondrial network, characterized by upregulated mitochondrial biogenesis and a downregulation of mitochondrial quality control (mitophagy), resulting in elevated numbers of small mitochondria with a depressed capacity for the generation of reactive oxygen species but improved capacity for ATP generation. These processes precondition cardiomyocyte mitochondria to be more resistant to IRI. Upon reperfusion, hearts with hβ3AR overexpression display a restoration in the mitochondrial quality control and a rapid activation of antioxidant responses. Strong protection against IRI was also observed in mice infected with an adeno-associated virus (AAV) encoding hβ3AR under a cardiomyocyte-specific promoter. These results confirm the translational potential of increased cardiomyocyte β3AR expression, achieved either naturally through exercise or artificially through gene therapy approaches, to precondition the cardiomyocyte mitochondrial network to withstand future insults.

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β3-肾上腺素能受体在心肌细胞中的过表达为线粒体承受缺血再灌注损伤提供了先决条件。
β3-肾上腺素能受体(β3AR)激动剂对缺血再灌注损伤(IRI)有保护作用。由于β3AR既存在于心肌细胞中,也存在于内皮细胞中,因此这种保护作用是由哪个细胞区段产生的一直不得而知。我们利用在心肌细胞或内皮细胞中组成性表达人 β3AR(hβ3AR)的转基因小鼠,在内源性 β3AR无效表达的遗传背景下研究发现,只有心肌细胞表达的β3AR才对 IRI(缺血 45 分钟,然后再灌注 24 小时)有保护作用。在内源性 β3AR 表达的基础上,心肌细胞过表达 hβ3AR 的小鼠在缺血再灌注后梗死面积也受到了限制。心肌细胞特异性β3AR过表达导致线粒体网络的基线重塑,其特点是线粒体生物生成上调,线粒体质量控制(丝裂噬)下调,导致小线粒体数量增加,活性氧生成能力下降,但 ATP 生成能力提高。这些过程为心肌细胞线粒体提供了先决条件,使其更能抵抗 IRI。再灌注时,过表达 hβ3AR 的心脏线粒体质量控制得到恢复,抗氧化反应迅速激活。用心肌细胞特异性启动子编码 hβ3AR 的腺相关病毒(AAV)感染小鼠后,也观察到了对 IRI 的强大保护作用。这些结果证实了增加心肌细胞β3AR表达的转化潜力,无论是通过运动自然实现,还是通过基因治疗方法人工实现,都能为心肌细胞线粒体网络预设条件,以抵御未来的损伤。
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来源期刊
Basic Research in Cardiology
Basic Research in Cardiology 医学-心血管系统
CiteScore
16.30
自引率
5.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Basic Research in Cardiology is an international journal for cardiovascular research. It provides a forum for original and review articles related to experimental cardiology that meet its stringent scientific standards. Basic Research in Cardiology regularly receives articles from the fields of - Molecular and Cellular Biology - Biochemistry - Biophysics - Pharmacology - Physiology and Pathology - Clinical Cardiology
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