棕色脂肪细胞 ADRB3 通过抑制外泌体 iNOS 介导心脏保护作用。

Brown Adipocyte ADRB3 Mediates Cardioprotection via Suppressing Exosomal iNOS.

机构信息

Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China (J.-R.L., L.-L.-Q.D., L.X., J.H., Z.-B.Z., X.-H.C., Y.-W.C., P.-J.G.).

Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai Key Laboratory of Bioactive Small Molecules, Fudan University, China (C.-C.R.).

出版信息

Circ Res. 2022 Jul 8;131(2):133-147. doi: 10.1161/CIRCRESAHA.121.320470. Epub 2022 Jun 2.

DOI:10.1161/CIRCRESAHA.121.320470

PMID:35652349

Abstract

BACKGROUND

The ADRB3 (β3-adrenergic receptors), which is predominantly expressed in brown adipose tissue (BAT), can activate BAT and improve metabolic health. Previous studies indicate that the endocrine function of BAT is associated with cardiac homeostasis and diseases. Here, we investigate the role of ADRB3 activation-mediated BAT function in cardiac remodeling.

METHODS

BKO (brown adipocyte-specific ADRB3 knockout) and littermate control mice were subjected to Ang II (angiotensin II) for 28 days. Exosomes from ADRB3 antagonist SR59230A (SR-exo) or agonist mirabegron (MR-exo) treated brown adipocytes were intravenously injected to Ang II-infused mice.

RESULTS

BKO markedly accelerated cardiac hypertrophy and fibrosis compared with control mice after Ang II infusion. In vitro, ADRB3 KO rather than control brown adipocytes aggravated expression of fibrotic genes in cardiac fibroblasts, and this difference was not detected after exosome inhibitor treatment. Consistently, BKO brown adipocyte-derived exosomes accelerated Ang II-induced cardiac fibroblast dysfunction compared with control exosomes. Furthermore, SR-exo significantly aggravated Ang II-induced cardiac remodeling, whereas MR-exo attenuated cardiac dysfunction. Mechanistically, ADRB3 KO or SR59230A treatment in brown adipocytes resulted an increase of iNOS (inducible nitric oxide synthase) in exosomes. Knockdown of iNOS in brown adipocytes reversed SR-exo-aggravated cardiac remodeling.

CONCLUSIONS

Our data illustrated a new endocrine pattern of BAT in regulating cardiac remodeling, suggesting that activation of ADRB3 in brown adipocytes offers cardiac protection through suppressing exosomal iNOS.

摘要

背景

ADRB3（β3-肾上腺素能受体）主要在棕色脂肪组织（BAT）中表达，可激活 BAT 并改善代谢健康。先前的研究表明，BAT 的内分泌功能与心脏内稳态和疾病有关。在这里，我们研究了 ADRB3 激活介导的 BAT 功能在心脏重构中的作用。

方法

BKO（棕色脂肪细胞特异性 ADRB3 敲除）和同窝对照小鼠接受 Ang II（血管紧张素 II）处理 28 天。ADRB3 拮抗剂 SR59230A（SR-exo）或激动剂米拉贝隆（MR-exo）处理的棕色脂肪细胞来源的外泌体通过静脉注射到 Ang II 输注的小鼠中。

结果

与 Ang II 输注后的对照小鼠相比，BKO 明显加速了心脏肥大和纤维化。在体外，ADRB3 KO 而不是对照棕色脂肪细胞加剧了心脏成纤维细胞中纤维化基因的表达，并且在用外泌体抑制剂处理后未检测到这种差异。一致地，BKO 棕色脂肪细胞衍生的外泌体加速了与对照外泌体相比 Ang II 诱导的心脏成纤维细胞功能障碍。此外，SR-exo 显著加重了 Ang II 诱导的心脏重构，而 MR-exo 则减轻了心脏功能障碍。机制上，ADRB3 KO 或 SR59230A 在棕色脂肪细胞中的处理导致外泌体中 iNOS（诱导型一氧化氮合酶）增加。在棕色脂肪细胞中敲低 iNOS 逆转了 SR-exo 加重的心脏重构。