Molecular Pharmacology Laboratory, Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
St Vincent's Clinical School, UNSW Sydney, Sydney, New South Wales, Australia.
Am J Physiol Heart Circ Physiol. 2021 Oct 1;321(4):H807-H817. doi: 10.1152/ajpheart.00198.2021. Epub 2021 Sep 17.
Multiple mouse lines lacking the orphan G protein-coupled receptor, GPR37L1, have elicited disparate cardiovascular phenotypes. The first knockout mice study to be published reported a marked elevation in systolic blood pressure (SBP; ∼60 mmHg), revealing a potential therapeutic opportunity. The phenotype differed from our own independently generated knockout line, where male mice exhibited equivalent baseline blood pressure to wild type. Here, we attempted to reproduce the first study by characterizing the cardiovascular phenotype of both the original knockout and transgenic lines alongside a C57BL/6J control line, using the same method of blood pressure measurement. The present study supports the findings from our independently developed knockout line, finding that SBP and diastolic blood pressure (DBP) are not different in the original knockout male mice (SBP: 130.9 ± 5.3 mmHg; DBP: 90.7 ± 3.0 mmHg) compared with C57BL/6J mice (SBP: 123.1 ± 4.1 mmHg; DBP: 87.0 ± 2.7 mmHg). Instead, we attribute the apparent hypertension of the knockout line originally described to comparison with a seemingly hypotensive transgenic line (SBP 103.7 ± 5.0 mmHg; DBP 71.9 ± 3.7 mmHg). Additionally, we quantified myocardial transcript in humans, which was suggested to be downregulated in cardiovascular disease. We found that has very low native transcript levels in human myocardium and that expression is not different in tissue samples from patients with heart failure compared with sex-matched healthy control tissue. These findings indicate that cardiac GPR37L1 expression is unlikely to contribute to the pathophysiology of human heart failure. This study characterizes systolic blood pressure (SBP) in a knockout mouse line, which was previously reported to have ∼60 mmHg higher SBP compared with a transgenic line. We observed only a ∼27 mmHg SBP difference between the lines. However, when compared with C57BL/6J mice, knockout mice showed no difference in SBP. We also investigated mRNA abundance in human hearts and observed no difference between healthy and failing heart samples.
多种缺乏孤儿 G 蛋白偶联受体 GPR37L1 的小鼠品系引起了不同的心血管表型。第一项发表的基因敲除小鼠研究报告称，收缩压（SBP；约 60mmHg）显著升高，揭示了潜在的治疗机会。表型与我们自己独立产生的基因敲除系不同，其中雄性小鼠的基础血压与野生型相当。在这里，我们试图通过对原始基因敲除和转基因系与 C57BL/6J 对照系的心血管表型进行特征描述，来重现第一项研究，使用相同的血压测量方法。本研究支持我们独立开发的基因敲除系的发现，发现原始基因敲除雄性小鼠的 SBP 和舒张压（DBP）与 C57BL/6J 小鼠没有差异（SBP：130.9±5.3mmHg；DBP：90.7±3.0mmHg）。相反，我们认为最初描述的基因敲除系的高血压是由于与看似低血压的转基因系进行比较的结果（SBP 103.7±5.0mmHg；DBP 71.9±3.7mmHg）。此外，我们还定量了人类心肌中的转录物，据报道该转录物在心血管疾病中下调。我们发现，在人类心肌中，有非常低的天然转录物水平，并且在心力衰竭患者的组织样本与性别匹配的健康对照组织相比，表达没有差异。这些发现表明，心脏 GPR37L1 的表达不太可能导致人类心力衰竭的病理生理学。本研究对以前报道的与转基因系相比 SBP 高约 60mmHg 的基因敲除小鼠系的 SBP 进行了特征描述。我们只观察到两条系之间约 27mmHg 的 SBP 差异。然而，与 C57BL/6J 小鼠相比，基因敲除小鼠的 SBP 没有差异。我们还研究了人类心脏中的 mRNA 丰度，并且在健康和衰竭心脏样本之间没有观察到差异。
