Deficiency of the sphingosine-1-phosphate (S1P) transporter Mfsd2b protects the heart against hypertension-induced cardiac remodeling by suppressing the L-type-Ca2+ channel.

IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Basic Research in Cardiology Pub Date : 2024-10-01 Epub Date: 2024-08-07 DOI:10.1007/s00395-024-01073-x
Dragos Andrei Duse, Nathalie Hannelore Schröder, Tanu Srivastava, Marcel Benkhoff, Jens Vogt, Melissa Kim Nowak, Florian Funk, Nina Semleit, Philipp Wollnitzke, Ralf Erkens, Sebastian Kötter, Sven Günther Meuth, Petra Keul, Webster Santos, Amin Polzin, Malte Kelm, Martina Krüger, Joachim Schmitt, Bodo Levkau
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Abstract

The erythrocyte S1P transporter Mfsd2b is also expressed in the heart. We hypothesized that S1P transport by Mfsd2b is involved in cardiac function. Hypertension-induced cardiac remodeling was induced by 4-weeks Angiotensin II (AngII) administration and assessed by echocardiography. Ca2+ transients and sarcomere shortening were examined in adult cardiomyocytes (ACM) from Mfsd2b+/+ and Mfsd2b-/- mice. Tension and force development were measured in skinned cardiac fibers. Myocardial gene expression was determined by real-time PCR, Protein Phosphatase 2A (PP2A) by enzymatic assay, and S1P by LC/MS, respectively. Msfd2b was expressed in the murine and human heart, and its deficiency led to higher cardiac S1P. Mfsd2b-/- mice had regular basal cardiac function but were protected against AngII-induced deterioration of left-ventricular function as evidenced by ~ 30% better stroke volume and cardiac index, and preserved ejection fraction despite similar increases in blood pressure. Mfsd2b-/- ACM exhibited attenuated Ca2+ mobilization in response to isoprenaline whereas contractility was unchanged. Mfsd2b-/- ACM showed no changes in proteins responsible for Ca2+ homeostasis, and skinned cardiac fibers exhibited reduced passive tension generation with preserved contractility. Verapamil abolished the differences in Ca2+ mobilization between Mfsd2b+/+ and Mfsd2b-/- ACM suggesting that S1P inhibits L-type-Ca2+ channels (LTCC). In agreement, intracellular S1P activated the inhibitory LTCC phosphatase PP2A in ACM and PP2A activity was increased in Mfsd2b-/- hearts. We suggest that myocardial S1P protects from hypertension-induced left-ventricular remodeling by inhibiting LTCC through PP2A activation. Pharmacologic inhibition of Mfsd2b may thus offer a novel approach to heart failure.

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缺乏鞘氨醇-1-磷酸(S1P)转运体 Mfsd2b 可通过抑制 L-type-Ca2+ 通道保护心脏免受高血压引起的心脏重塑的影响。
红细胞 S1P 转运体 Mfsd2b 也在心脏中表达。我们假设 Mfsd2b 转运的 S1P 参与了心脏功能。高血压诱导的心脏重塑是通过4周的血管紧张素II(AngII)给药诱导的,并通过超声心动图进行评估。在来自 Mfsd2b+/+ 和 Mfsd2b-/- 小鼠的成体心肌细胞(ACM)中检测了 Ca2+ 瞬时和肌节缩短。对带皮心肌纤维的张力和肌力发展进行了测量。心肌基因表达分别通过实时 PCR 法、蛋白磷酸酶 2A (PP2A) 酶法和 S1P LC/MS 法进行测定。Msfd2b在小鼠和人类心脏中均有表达,其缺乏会导致心脏S1P升高。Mfsd2b-/-小鼠的基础心脏功能正常,但对AngII诱导的左心室功能恶化有保护作用,表现为尽管血压升高相似,但每搏量和心脏指数提高约30%,射血分数保持不变。Mfsd2b-/- ACM 对异丙肾上腺素的 Ca2+ 迁移反应减弱,而收缩力保持不变。Mfsd2b-/- ACM中负责Ca2+平衡的蛋白质没有变化,带皮心肌纤维表现出被动张力生成减少,但收缩力保持不变。维拉帕米消除了 Mfsd2b+/+ 和 Mfsd2b-/- ACM 之间 Ca2+ 迁移的差异,这表明 S1P 可抑制 L 型-Ca2+ 通道(LTCC)。同样,细胞内 S1P 激活了 ACM 中抑制 LTCC 的磷酸酶 PP2A,而在 Mfsd2b-/- 心脏中 PP2A 活性增加。我们认为,心肌 S1P 可通过 PP2A 激活抑制 LTCC,从而防止高血压引起的左心室重构。因此,药物抑制 Mfsd2b 可能是治疗心力衰竭的一种新方法。
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来源期刊
Basic Research in Cardiology
Basic Research in Cardiology 医学-心血管系统
CiteScore
16.30
自引率
5.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Basic Research in Cardiology is an international journal for cardiovascular research. It provides a forum for original and review articles related to experimental cardiology that meet its stringent scientific standards. Basic Research in Cardiology regularly receives articles from the fields of - Molecular and Cellular Biology - Biochemistry - Biophysics - Pharmacology - Physiology and Pathology - Clinical Cardiology
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