Messaoudi Smail, He Ying, Gutsol Alex, Wight Andrew, Hébert Richard L, Vilmundarson Ragnar O, Makrigiannis Andrew P, Chalmers John, Hamet Pavel, Tremblay Johanne, McPherson Ruth, Stewart Alexandre F R, Touyz Rhian M, Nemer Mona
Faculty of Medicine, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5.
Kidney Research Center, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H8M5.
Nat Commun. 2015 Nov 30;6:8835. doi: 10.1038/ncomms9835.
Despite its high prevalence and economic burden, the aetiology of human hypertension remains incompletely understood. Here we identify the transcription factor GATA5, as a new regulator of blood pressure (BP). GATA5 is expressed in microvascular endothelial cells and its genetic inactivation in mice (Gata5-null) leads to vascular endothelial dysfunction and hypertension. Endothelial-specific inactivation of Gata5 mimics the hypertensive phenotype of the Gata5-null mice, suggestive of an important role for GATA5 in endothelial homeostasis. Transcriptomic analysis of human microvascular endothelial cells with GATA5 knockdown reveals that GATA5 affects several genes and pathways critical for proper endothelial function, such as PKA and nitric oxide pathways. Consistent with a role in human hypertension, we report genetic association of variants at the GATA5 locus with hypertension traits in two large independent cohorts. Our results unveil an unsuspected link between GATA5 and a prominent human condition, and provide a new animal model for hypertension.
尽管人类高血压患病率高且负担沉重，但其病因仍未完全明确。在此，我们确定转录因子GATA5为血压（BP）的新调节因子。GATA5在微血管内皮细胞中表达，其在小鼠中的基因失活（Gata5基因敲除）会导致血管内皮功能障碍和高血压。Gata5在内皮细胞特异性失活模拟了Gata5基因敲除小鼠的高血压表型，提示GATA5在内皮细胞稳态中起重要作用。对GATA5敲低的人微血管内皮细胞进行转录组分析发现，GATA5影响几个对内皮功能正常至关重要的基因和信号通路，如蛋白激酶A和一氧化氮信号通路。与在人类高血压中的作用一致，我们报告了在两个大型独立队列中GATA5基因座变异与高血压性状的遗传关联。我们的结果揭示了GATA5与一种常见人类疾病之间未曾预料到的联系，并提供了一种新的高血压动物模型。
