Mechanisms of Macrophage Foam Cell Formation and Hypertensive Complications Caused by Vasoactive Agents

本研究阐明了新型血管活性药物如尿紧张素II和salusins引起巨噬细胞泡沫细胞形成和动脉粥样硬化的机制。进一步，我们研究了这些血管活性药物与高血压或动脉粥样硬化疾病之间的关系。Urotensin II是迄今为止最有效的血管收缩肽，通过上调人单核细胞源性巨噬细胞的酰基辅酶a：胆固醇酰基转移酶-1 （ACAT1）来加速泡沫细胞的形成。当与血清素、氧化低密度脂蛋白或活性氧联合使用时，Urotensin II还能刺激血管平滑肌细胞（VSMC）的增殖，并具有协同效应。原发性高血压患者血浆尿紧张素II水平与收缩血水平呈正相关。同样的前体（pre - pro-salusin），最近被发现为新的血管活性肽。Salusin-β具有较强的降压作用。salusin-β通过上调ACAT1促进人巨噬细胞泡沫细胞的形成，salusin-a通过下调ACAT1抑制巨噬细胞泡沫细胞的形成。在人冠状动脉粥样硬化斑块中检测到免疫反应性salusin-a和salusin-β， salusin-β在VSMCs、成纤维细胞和巨噬细胞泡沫细胞中占主导地位。急性冠脉综合征（ACS）、稳定型心绞痛或心肌梗死后患者血清salusin-a水平低于高血压患者或健康志愿者。ACS患者血清salusin-α水平最低，且随冠脉病变严重程度降低。高血压患者血清salusin-α水平略低于健康志愿者，且与颈动脉病变严重程度呈负相关。研究结果表明，血管活性药物可调节高血压患者动脉粥样硬化的进展，可能是动脉粥样硬化疾病的候选生物标志物。

The present study clarified the mechanisms of macrophage foam cell formation and atherosclerosis caused by new vasoactive agents, such as urotensin II and salusins. Further, we studied the relationships between these vasoactive agents and hypertension or atherosclerotic diseases.Urotensin II, the most potent vasoconstrictor peptide to date, accelerated foam cell formation via up-regulating acyl-CoA: cholesterol acyltransferase-1 (ACAT1) inhumanmonocyte-derivedmacrophages. Urotensin II also stimulated vascular smooth muscle cell (VSMC) proliferation with synergistic effects observed when combined with serotonin, oxidized low-density lipoprotein, or reactive oxygen species. In patients with essential hypertension, plasma levels of urotensin II were positively correlated with systolic blood 〓.the same precursor (prepro-salusin), were recently discovered as new vasoactive peptides. Salusin-β exerted the potent hypotensive effects. Human macrophage foam cell formation was enhanced by salusin-β via up-regulating ACAT1, whereas was reduced by salusin-a via down-regulating ACAT1. Immunoreactive salusin-a and salusin-β were detected in human coronary atherosclerotic plaques, with dominance of salusin-β in VSMCs, fibroblasts, and macrophage-foam cells. Serum levels of salusin-a were decreased in patients with acute coronary syndrome (ACS), stable effort angina pectoris, or post myocardial infarction than in hypertensive patients or healthy volunteers. Among these groups, serum salusin-α levels were the lowest in ACS patients and their salusin-α levels were decreased in accordance with the severity of coronary artery lesions. Serum salusin-α levels in hypertensive patients were slightly lower compared with that in healthy volunteers, and were negatively correlated with the severity of carotid 〓 findings suggest that vasoactive agents modulate the progression of atherosclerosis in hypertension and may be a candidate for biomarkers of atherosclerotic diseases.