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-1β 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·kg-1·d-1 subcutaneous) for 14 days. To accelerate the development of atherosclerosis, apolipoprotein E knockout mice were infused with angiotensin II (0.72 mg·kg-1·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.

中文翻译：

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短链脂肪酸丙酸酯可预防高血压性心血管损害。

背景技术动脉高血压及其器官后遗症表现出T细胞介导的炎性疾病的特征。实验性抗炎疗法已被证明可减轻高血压性终末器官损害。最近，针对白介素-1β的CANTOS研究（Canakinumab抗炎血栓形成结果研究）证明抗炎治疗降低了心血管疾病的风险。肠道微生物组在免疫稳态和心血管健康中起着关键作用。短链脂肪酸（SCFA）是由肠道细菌从膳食纤维中产生的，并影响宿主的免疫稳态。在这里，我们研究了SCFA丙酸酯在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SCFA对高血压性心脏损害和动脉粥样硬化的影响，野生型NMRI或载脂蛋白E基因敲除缺陷型小鼠在饮用水中接受了丙酸盐（200 mmol / L）或对照组。为诱发高血压，向野生型NMRI小鼠皮下注射血管紧张素II（1.44 mg·kg-1·d-1）14天。为促进动脉粥样硬化的发展，将载脂蛋白E基因敲除的小鼠皮下注射血管紧张素II（0.72 mg·kg-1·d-1皮下注射）28天。使用组织学，超声心动图，体内电生理学，免疫荧光和流式细胞仪评估心脏损伤和动脉粥样硬化。血压通过无线电遥测法测量。使用PC61抗体的调节性T细胞耗竭被用于检查丙酸酯的作用方式。结果在两种模型中，丙酸酯均可显着减轻心脏肥大，纤维化，血管功能障碍和高血压。在丙酸处理的血管紧张素II注入的野生型NMRI小鼠中，对心脏室性心律不齐的敏感性显着降低。在丙酸处理的载脂蛋白E基因敲除缺陷小鼠中，主动脉粥样硬化病变面积明显减少。全身性炎症通过丙酸治疗得到缓解，量化为两种模型中脾效应记忆T细胞频率和脾T辅助17细胞的减少，以及野生型NMRI小鼠局部心脏免疫细胞浸润的减少。在输注调节性T细胞的血管紧张素II小鼠中取消了丙酸酯的心脏保护作用，表明该作用是调节性T细胞依赖性的。结论我们的数据强调了SCFA的免疫调节作用及其对心血管健康的重要性。