Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage
Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage
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DOI：
10.1161/circulationaha.118.036652
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发表时间：
2019-03-12
期刊：
影响因子：
37.8
通讯作者：
Wilck, Nicola
中科院分区：
文献类型：
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作者：
Bartolomaeus, Hendrik;Balogh, Andras;Wilck, Nicola
背景：动脉高血压及其器官后遗症表现出T细胞介导的炎症性疾病的特征。实验性抗炎疗法已被证明可改善高血压终末器官损伤。最近，针对白细胞介素-1 β的CANTOS研究（Canakinumab抗炎血栓结局研究）表明，抗炎治疗可降低心血管风险。肠道微生物群在免疫稳态和心血管健康中起着关键作用。短链脂肪酸（SCFAs）是肠道细菌从膳食纤维中产生的一种影响宿主免疫稳态的物质。在这里，我们研究了丙酸SCFA在2种不同的高血压心血管损伤小鼠模型中的作用。方法：为了研究SCFAs对高血压心脏损伤和动脉粥样硬化的影响，野生型NMRI或载脂蛋白E敲除缺陷小鼠接受丙酸（200 mmol/L）或对照的饮用水。为了诱导高血压，野生型NMRI小鼠注射血管紧张素II （1.44 mg中心点kg（-1）中心点d（-1）皮下注射）14天。为了加速动脉粥样硬化的发展，载脂蛋白E敲除小鼠注射血管紧张素II （0.72 mg中心点kg（-1）中心点d（-1）皮下注射）28天。采用组织学、超声心动图、体内电生理、免疫荧光和流式细胞术评估心脏损伤和动脉粥样硬化。用无线电遥测法测量血压。利用PC61抗体的调节性T细胞耗竭检测丙酸盐的作用方式。结果：丙酸可显著减轻两种模型的心肌肥厚、纤维化、血管功能障碍和高血压。灌注丙酸治疗的血管紧张素ii野生型NMRI小鼠对室性心律失常的易感性显著降低。丙酸处理的载脂蛋白E敲除缺陷小鼠主动脉粥样硬化病变面积显著减少。在两种模型中，丙酸治疗减轻了全身炎症，量化为脾脏效应记忆T细胞频率和脾脏T辅助17细胞的减少，野生型NMRI小鼠局部心脏免疫细胞浸润的减少。在调节性T细胞衰竭的血管紧张素ii输注小鼠中，丙酸盐的心脏保护作用被取消，表明其作用依赖于调节性T细胞。结论：我们的数据强调了SCFAs的免疫调节作用及其对心血管健康的重要性。数据表明，生活方式的改变导致SCFA生成的增加可能是高血压心血管疾病患者有益的非药物预防策略。
BACKGROUND: Arterial hypertension and its organ sequelae show characteristics of T cell-mediated inflammatory diseases. Experimental anti-inflammatory therapies have been shown to ameliorate hypertensive end-organ damage. Recently, the CANTOS study (Canakinumab Antiinflammatory Thrombosis Outcome Study) targeting interleukin-1 beta demonstrated that anti-inflammatory therapy reduces cardiovascular risk. The gut microbiome plays a pivotal role in immune homeostasis and cardiovascular health. Short-chain fatty acids (SCFAs) are produced from dietary fiber by gut bacteria and affect host immune homeostasis. Here, we investigated effects of the SCFA propionate in 2 different mouse models of hypertensive cardiovascular damage.METHODS: To investigate the effect of SCFAs on hypertensive cardiac damage and atherosclerosis, wild-type NMRI or apolipoprotein E knockout-deficient mice received propionate (200 mmol/L) or control in the drinking water. To induce hypertension, wild-type NMRI mice were infused with angiotensin II (1.44 mg center dot kg(-1)center dot d(-1) subcutaneous) for 14 days. To accelerate the development of atherosclerosis, apolipoprotein E knockout mice were infused with angiotensin II (0.72 mg center dot kg(-1)center dot d(-1) subcutaneous) for 28 days. Cardiac damage and atherosclerosis were assessed using histology, echocardiography, in vivo electrophysiology, immunofluorescence, and flow cytometry. Blood pressure was measured by radiotelemetry. Regulatory T cell depletion using PC61 antibody was used to examine the mode of action of propionate.RESULTS: Propionate significantly attenuated cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension in both models. Susceptibility to cardiac ventricular arrhythmias was significantly reduced in propionate-treated angiotensin II-infused wild-type NMRI mice. Aortic atherosclerotic lesion area was significantly decreased in propionate-treated apolipoprotein E knockout-deficient mice. Systemic inflammation was mitigated by propionate treatment, quantified as a reduction in splenic effector memory T cell frequencies and splenic T helper 17 cells in both models, and a decrease in local cardiac immune cell infiltration in wild-type NMRI mice. Cardioprotective effects of propionate were abrogated in regulatory T cell-depleted angiotensin II-infused mice, suggesting the effect is regulatory T cell-dependent.CONCLUSIONS: Our data emphasize an immune-modulatory role of SCFAs and their importance for cardiovascular health. The data suggest that lifestyle modifications leading to augmented SCFA production could be a beneficial nonpharmacological preventive strategy for patients with hypertensive cardiovascular disease.