Experimental Research Laboratory, Heart and Vascular Center, Semmelweis University, Városmajor u. 68., 1122, Budapest, Hungary.
Department of Physiology, Semmelweis University, Budapest, Hungary.
Cardiovasc Diabetol. 2020 Sep 30;19(1):159. doi: 10.1186/s12933-020-01141-1.
Whereas selective sodium-glucose cotransporter 2 (SGLT2) inhibitors consistently showed cardiovascular protective effects in large outcome trials independent of the presence of type 2 diabetes mellitus (T2DM), the cardiovascular effects of dual SGLT1/2 inhibitors remain to be elucidated. Despite its clinical relevance, data are scarce regarding left ventricular (LV) SGLT1 expression in distinct heart failure (HF) pathologies. We aimed to characterize LV SGLT1 expression in human patients with end-stage HF, in context of the other two major glucose transporters: GLUT1 and GLUT4.
Control LV samples (Control, n = 9) were harvested from patients with preserved LV systolic function who went through mitral valve replacement. LV samples from HF patients undergoing heart transplantation (n = 71) were obtained according to the following etiological subgroups: hypertrophic cardiomyopathy (HCM, n = 7); idiopathic dilated cardiomyopathy (DCM, n = 12); ischemic heart disease without T2DM (IHD, n = 14), IHD with T2DM (IHD + T2DM, n = 11); and HF patients with cardiac resynchronization therapy (DCM:CRT, n = 9, IHD:CRT, n = 9 and IHD-T2DM:CRT, n = 9). We measured LV SGLT1, GLUT1 and GLUT4 gene expressions with qRT-PCR. The protein expression of SGLT1, and activating phosphorylation of AMP-activated protein kinase (AMPKα) and extracellular signal-regulated kinase 1/2 (ERK1/2) were quantified by western blotting. Immunohistochemical staining of SGLT1 was performed.
Compared with controls, LV SGLT1 mRNA and protein expressions were significantly and comparably upregulated in HF patients with DCM, IHD and IHD + T2DM (all P < 0.05), but not in HCM. LV SGLT1 mRNA and protein expressions positively correlated with LVEDD and negatively correlated with EF (all P < 0.01). Whereas AMPKα phosphorylation was positively associated with SGLT1 protein expression, ERK1/2 phosphorylation showed a negative correlation (both P < 0.01). Immunohistochemical staining revealed that SGLT1 expression was predominantly confined to cardiomyocytes, and not fibrotic tissue. Overall, CRT was associated with reduction of LV SGLT1 expression, especially in patients with DCM.
Myocardial LV SGLT1 is upregulated in patients with HF (except in those with HCM), correlates significantly with parameters of cardiac remodeling (LVEDD) and systolic function (EF), and is downregulated in DCM patients with CRT. The possible role of SGLT1 in LV remodeling needs to be elucidated.
尽管选择性钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂在大型结局试验中独立于 2 型糖尿病（T2DM）存在，表现出心血管保护作用，但双重 SGLT1/2 抑制剂的心血管作用仍有待阐明。尽管具有临床相关性，但有关心力衰竭（HF）不同病理中的左心室（LV）SGLT1 表达的数据仍然很少。我们旨在描述终末期 HF 患者的 LV SGLT1 表达情况，并将其与其他两种主要的葡萄糖转运蛋白：GLUT1 和 GLUT4 进行比较。
从接受二尖瓣置换术的保留 LV 收缩功能的患者中采集对照 LV 样本（对照组，n=9）。根据以下病因亚组从接受心脏移植的 HF 患者中获取 LV 样本：肥厚型心肌病（HCM，n=7）；特发性扩张型心肌病（DCM，n=12）；无 T2DM 的缺血性心脏病（IHD，n=14），有 T2DM 的缺血性心脏病（IHD+T2DM，n=11）；以及接受心脏再同步治疗的 HF 患者（DCM：CRT，n=9，IHD：CRT，n=9 和 IHD-T2DM：CRT，n=9）。我们使用 qRT-PCR 测量 LV SGLT1、GLUT1 和 GLUT4 的基因表达。通过 Western 印迹定量测定 SGLT1 的蛋白表达以及 AMP 激活蛋白激酶（AMPKα）和细胞外信号调节激酶 1/2（ERK1/2）的激活磷酸化。进行 SGLT1 的免疫组织化学染色。
与对照组相比，DCM、IHD 和 IHD+T2DM 患者的 LV SGLT1 mRNA 和蛋白表达显著上调（均 P<0.05），但 HCM 患者没有。LV SGLT1 mRNA 和蛋白表达与 LVEDD 呈正相关，与 EF 呈负相关（均 P<0.01）。AMPKα 磷酸化与 SGLT1 蛋白表达呈正相关，而 ERK1/2 磷酸化呈负相关（均 P<0.01）。免疫组织化学染色显示 SGLT1 表达主要局限于心肌细胞，而不是纤维化组织。总的来说，CRT 与 LV SGLT1 表达的降低有关，尤其是在 DCM 患者中。
HF 患者的心肌 LV SGLT1 上调（HCM 患者除外），与心脏重构（LVEDD）和收缩功能（EF）的参数显著相关，DCM 患者接受 CRT 后 SGLT1 表达下调。SGLT1 在 LV 重构中的可能作用需要进一步阐明。
