Sergienko Nicola M, Trewin Adam J, Kiriazis Helen, Raaijmakers Antonia J A, Donner Daniel G, Garside Victoria C, Smith Kelly A, Bell James R, Mellor Kimberley M, Delbridge Lea M D, McMullen Julie R, Weeks Kate L
Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Department of Diabetes, Central Clinical School, Monash University, Clayton, Victoria, Australia.
NPJ Metab Health Dis. 2024 Nov 6;2(1):32. doi: 10.1038/s44324-024-00033-2.
Protein phosphatase 2A (PP2A) regulatory subunit B55α has been implicated in the transcriptional regulation of cardiac growth and fibrosis by suppressing HDAC5/MEF2 signalling in cardiomyocytes. We created and characterised two mouse models with global or cardiomyocyte-specific disruption of the gene encoding B55α (Ppp2r2a) to conduct the first detailed exploration of B55α in the heart. Global homozygous B55α knockout mice died in utero, while heterozygous mice had thinner left ventricular walls at 12 months, an effect more pronounced in males. At 10-12 weeks of age, cardiomyocyte-specific B55α knockout mice displayed normal cardiac morphology with increased left ventricular collagen deposition, identifying B55α as a negative regulator of cardiac fibrosis. Gene expression analyses demonstrated extensive remodelling of the cardiac transcriptome in male but not female mice, revealing a sexually dimorphic role for B55α in cardiac transcriptional regulation. These findings provide a basis for future work investigating B55α in cardiac stress settings.
蛋白磷酸酶2A（PP2A）调节亚基B55α通过抑制心肌细胞中的HDAC5/MEF2信号传导，参与心脏生长和纤维化的转录调控。我们构建并鉴定了两种小鼠模型，分别为编码B55α（Ppp2r2a）的基因在全身或心肌细胞特异性缺失的模型，以首次对心脏中的B55α进行详细研究。全身纯合B55α基因敲除小鼠在子宫内死亡，而异合子小鼠在12个月时左心室壁更薄，这种效应在雄性小鼠中更明显。在10-12周龄时，心肌细胞特异性B55α基因敲除小鼠表现出正常的心脏形态，但左心室胶原沉积增加，表明B55α是心脏纤维化的负调节因子。基因表达分析表明，雄性而非雌性小鼠的心脏转录组发生了广泛重塑，揭示了B55α在心脏转录调控中的性别差异作用。这些发现为未来在心脏应激环境中研究B55α奠定了基础。
