Effects of canagliflozin on human myocardial redox signalling: clinical implications.
Effects of canagliflozin on human myocardial redox signalling: clinical implications.
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DOI：
10.1093/eurheartj/ehab420
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发表时间：
2021-12-21
影响因子：
39.3
通讯作者：
Antoniades C
中科院分区：
文献类型：
--
作者：
Kondo H;Akoumianakis I;Badi I;Akawi N;Kotanidis CP;Polkinghorne M;Stadiotti I;Sommariva E;Antonopoulos AS;Carena MC;Oikonomou EK;Reus EM;Sayeed R;Krasopoulos G;Srivastava V;Farid S;Chuaiphichai S;Shirodaria C;Channon KM;Casadei B;Antoniades C
最近的临床试验表明，钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂可改善心力衰竭患者的心血管结局，但其潜在机制仍不清楚。我们探讨了卡格列净（一种具有轻度 SGLT1 抑制作用的 SGLT2 抑制剂）对人类心肌氧化还原信号传导的直接影响。研究 1 纳入了 364 名接受心脏手术的患者。采集右心耳活组织检查以量化超氧化物（）来源以及炎症、纤维化和心肌拉伸基因的表达。在研究 2 中，使用离体 51 名患者的心房组织来研究卡格列净对 NADPH 氧化酶活性和一氧化氮合酶 (NOS) 解偶联的直接影响。分化的 H9C2 和原代人心肌细胞 (hCM) 用于进一步表征潜在机制（研究 3）。与 SGLT2 相反，SGLT1 在人类心房组织和 hCM 中大量表达。心肌 SGLT1 表达与促纤维化、促炎症和壁拉伸基因表达呈正相关。 Canagliflozin 通过 AMP 激酶 (AMPK)/Rac1 信号传导降低 NADPH 氧化酶活性，并通过增加四氢生物蝶呤的体外和体外生物利用度改善 NOS 偶联。通过敲低 hCM 中的 SGLT1 可以减弱这些作用。 Canagliflozin 对心肌氧化还原信号传导具有显着的离体转录组效应，可抑制 hCM 中的细胞凋亡和炎症通路。我们首次证明卡格列净通过 SGLT1/AMPK/Rac1 信号传导抑制心肌 NADPH 氧化酶活性并改善 NOS 偶联，从而在人类心肌中产生全面的抗炎和抗凋亡作用。这些发现揭示了卡格列净对心脏有益作用的新机制。提出卡格列净诱导心肌氧化还原状态改善的机制。 Canagliflozin 通过抑制 SGLT1 增加细胞内 AMP/ATP 比率，SGLT1 可以激活 AMPK/NOS 信号传导并增加 NO，从而抑制促炎信号传导。 AMPK 激活还抑制 Rac1 的激活以及 Rac1 和 p47phox 的膜易位，从而降低 NADPH 氧化酶活性和超氧化物 () 产生，减弱炎症和细胞凋亡途径，并增加四氢生物蝶呤 (BH4)（NOS 偶联的关键因素）的生物利用度。
Recent clinical trials indicate that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in heart failure patients, but the underlying mechanisms remain unknown. We explored the direct effects of canagliflozin, an SGLT2 inhibitor with mild SGLT1 inhibitory effects, on myocardial redox signalling in humans. Study 1 included 364 patients undergoing cardiac surgery. Right atrial appendage biopsies were harvested to quantify superoxide () sources and the expression of inflammation, fibrosis, and myocardial stretch genes. In Study 2, atrial tissue from 51 patients was used ex vivo to study the direct effects of canagliflozin on NADPH oxidase activity and nitric oxide synthase (NOS) uncoupling. Differentiated H9C2 and primary human cardiomyocytes (hCM) were used to further characterize the underlying mechanisms (Study 3). SGLT1 was abundantly expressed in human atrial tissue and hCM, contrary to SGLT2. Myocardial SGLT1 expression was positively associated with production and pro-fibrotic, pro-inflammatory, and wall stretch gene expression. Canagliflozin reduced NADPH oxidase activity via AMP kinase (AMPK)/Rac1signalling and improved NOS coupling via increased tetrahydrobiopterin bioavailability ex vivo and in vitro. These were attenuated by knocking down SGLT1 in hCM. Canagliflozin had striking ex vivo transcriptomic effects on myocardial redox signalling, suppressing apoptotic and inflammatory pathways in hCM. We demonstrate for the first time that canagliflozin suppresses myocardial NADPH oxidase activity and improves NOS coupling via SGLT1/AMPK/Rac1 signalling, leading to global anti-inflammatory and anti-apoptotic effects in the human myocardium. These findings reveal a novel mechanism contributing to the beneficial cardiac effects of canagliflozin. Proposed mechanism of canagliflozin-induced improvement of myocardial redox state. Canagliflozin increases intracellular AMP/ATP ratio through inhibition of SGLT1, which can activate AMPK/NOS signalling and increase NO that suppresses pro-inflammatory signalling. AMPK activation also inhibits activation of Rac1 and membrane translocation of Rac1 and p47phox, which decrease NADPH oxidase activity and superoxide () production, attenuates inflammatory and apoptotic pathways and increasing the bioavailability of tetrahydrobiopterin (BH4), a key factor for NOS coupling.
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影响因子：
2.9
作者：
Devineni, Damayanthi;Curtin, Christopher R.;Rothenberg, Paul L.
通讯作者：
Rothenberg, Paul L.
影响因子：
4.6
作者：
Mancini SJ;Boyd D;Katwan OJ;Strembitska A;Almabrouk TA;Kennedy S;Palmer TM;Salt IP
通讯作者：
Salt IP
影响因子：
24
作者：
Antoniades, Charalambos;Demosthenous, Michael;Casadei, Barbara
通讯作者：
Casadei, Barbara
影响因子：
5.4
作者：
Danne, Thomas;Biester, Torben;Kordonouri, Olga
通讯作者：
Kordonouri, Olga
影响因子：
3.5
作者：
Di Franco, Alessandra;Cantini, Giulia;Mannucci, Edoardo
通讯作者：
Mannucci, Edoardo