Dean Afshan, Nilsen Margaret, Loughlin Lynn, Salt Ian P, MacLean Margaret R
From the Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Hypertension. 2016 Aug;68(2):446-54. doi: 10.1161/HYPERTENSIONAHA.116.07353. Epub 2016 Jun 13.
Females are more susceptible to pulmonary arterial hypertension than males, although the reasons remain unclear. The hypoglycemic drug, metformin, is reported to have multiple actions, including the inhibition of aromatase and stimulation of AMP-activated protein kinase. Inhibition of aromatase using anastrazole is protective in experimental pulmonary hypertension but whether metformin attenuates pulmonary hypertension through this mechanism remains unknown. We investigated whether metformin affected aromatase activity and if it could reduce the development of pulmonary hypertension in the sugen 5416/hypoxic rat model. We also investigated its influence on proliferation in human pulmonary arterial smooth muscle cells. Metformin reversed right ventricular systolic pressure, right ventricular hypertrophy, and decreased pulmonary vascular remodeling in the rat. Furthermore, metformin increased rat lung AMP-activated protein kinase signaling, decreased lung and circulating estrogen levels, levels of aromatase, the estrogen metabolizing enzyme; cytochrome P450 1B1 and its transcription factor; the aryl hydrocarbon receptor. In human pulmonary arterial smooth muscle cells, metformin decreased proliferation and decreased estrogen synthesis by decreasing aromatase activity through the PII promoter site of Cyp19a1 Thus, we report for the first time that metformin can reverse pulmonary hypertension through inhibition of aromatase and estrogen synthesis in a manner likely to be mediated by AMP-activated protein kinase.
女性比男性更容易患肺动脉高压，尽管其原因尚不清楚。据报道，降糖药物二甲双胍具有多种作用，包括抑制芳香化酶和刺激AMP激活的蛋白激酶。使用阿那曲唑抑制芳香化酶在实验性肺动脉高压中具有保护作用，但二甲双胍是否通过该机制减轻肺动脉高压仍不清楚。我们研究了二甲双胍是否影响芳香化酶活性，以及它是否能减少sugen 5416/低氧大鼠模型中肺动脉高压的发展。我们还研究了其对人肺动脉平滑肌细胞增殖的影响。二甲双胍逆转了大鼠的右心室收缩压、右心室肥大，并减少了肺血管重塑。此外，二甲双胍增加了大鼠肺中AMP激活的蛋白激酶信号传导，降低了肺和循环中的雌激素水平、芳香化酶水平、雌激素代谢酶细胞色素P450 1B1及其转录因子芳烃受体的水平。在人肺动脉平滑肌细胞中，二甲双胍通过降低Cyp19a1的PII启动子位点的芳香化酶活性来减少增殖并降低雌激素合成。因此，我们首次报道二甲双胍可以通过抑制芳香化酶和雌激素合成以一种可能由AMP激活的蛋白激酶介导的方式逆转肺动脉高压。
