Characterization of left ventricular myocardial sodium-glucose cotransporter 1 expression in patients with end-stage heart failure

Sayour, Alex Ali; Oláh, Attila; Ruppert, Mihály; Barta, Bálint András; Horváth, Eszter; Benke, Kálmán; Pólos, Miklós; Hartyánszky, István; Merkely, Béla; Radovits, Tamás

doi:10.1186/s12933-020-01141-1

Cited by 31 publications

(40 citation statements)

References 54 publications

(102 reference statements)

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“…The myocardial expression of SGLT1 in humans is altered in various cardiovascular disease states. Compared with controls, left ventricular SGLT1 mRNA and protein expression was significantly upregulated in heart failure patients with DCM ( Sayour et al, 2020 ). Individuals carrying loss-of-function mutations in the SGLT1 gene are estimated to have a lower risk of developing heart failure, driven by mitigation of postprandial hyperglycemic episodes ( Seidelmann et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

et al. 2021

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Background: Cardiac fibroblast (CF) activation is a hallmark feature of cardiac fibrosis in diabetic cardiomyopathy (DCM). Inhibition of the sodium-dependent glucose transporter 1 (SGLT1) attenuates cardiomyocyte apoptosis and delays the development of DCM. However, the role of SGLT1 in CF activation remains unclear.Methods: A rat model of DCM was established and treated with si‐SGLT1 to examine cardiac fibrosis. In addition, in vitro experiments were conducted to verify the regulatory role of SGLT1 in proliferation and collagen secretion in high-glucose– (HG–) treated CFs.Results: SGLT1 was found to be upregulated in diabetic cardiac tissues and HG-induced CFs. HG stimulation resulted in increased proliferation and migration, increased the expression of transforming growth factor-β1 and collagen I and collagen III, and increased phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) 1/2. These trends in HG-treated CFs were significantly reversed by si-SGLT1. Moreover, the overexpression of SGLT1 promoted CF proliferation and collagen synthesis and increased phosphorylation of p38 mitogen-activated protein kinase and ERK1/2. SGLT1 silencing significantly alleviated cardiac fibrosis, but had no effect on cardiac hypertrophy in diabetic hearts.Conclusion: These findings provide new information on the role of SGLT1 in CF activation, suggesting a novel therapeutic strategy for the treatment of DCM fibrosis.

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Section: Discussionmentioning

confidence: 99%

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

et al. 2021

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“…This last effect was also documented in studies which showed no infarct size-limiting effect [ 21 , 22 ]. Because SGLT2 expression is negligible in the heart under normal and pathological conditions [ 23 , 24 ], off-target mechanisms have been suggested [ 1 , 12 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Sodium–glucose cotransporter 2 inhibitors reduce myocardial infarct size in preclinical animal models of myocardial ischaemia–reperfusion injury: a meta-analysis

et al. 2021

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Aims/hypothesis Large cardiovascular outcome trials demonstrated that the cardioprotective effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors might reach beyond glucose-lowering action. In this meta-analysis, we sought to evaluate the potential infarct size-modulating effect of SGLT2 inhibitors in preclinical studies. Methods In this preregistered meta-analysis (PROSPERO: CRD42020189124), we included placebo-controlled, interventional studies of small and large animal models of myocardial ischaemia–reperfusion injury, testing the effect of SGLT2 inhibitor treatment on myocardial infarct size (percentage of area at risk or total area). Standardised mean differences (SMDs) were calculated and pooled using random-effects method. We evaluated heterogeneity by computing Τ2 and I2 values. Meta-regression was performed to explore prespecified subgroup differences according to experimental protocols and their contribution to heterogeneity was assessed (pseudo-R2 values). Results We identified ten eligible publications, reporting 16 independent controlled comparisons on a total of 224 animals. Treatment with SGLT2 inhibitor significantly reduced myocardial infarct size compared with placebo (SMD = −1.30 [95% CI −1.79, −0.81], p < 0.00001), referring to a 33% [95% CI 20%, 47%] difference. Heterogeneity was moderate (Τ2 = 0.58, I2 = 60%). SGLT2 inhibitors were only effective when administered to the intact organ system, but not to isolated hearts (p interaction <0.001, adjusted pseudo-R2 = 47%). While acute administration significantly reduced infarct size, chronic treatment was superior (p interaction <0.001, adjusted pseudo-R2 = 85%). The medications significantly reduced infarct size in both diabetic and non-diabetic animals, favouring the former (p interaction = 0.030, adjusted pseudo-R2 = 12%). Treatment was equally effective in rats and mice, as well as in a porcine model. Individual study quality scores were not related to effect estimates (p = 0.33). The overall effect estimate remained large even after adjusting for severe forms of publication bias. Conclusions/interpretation The glucose-lowering SGLT2 inhibitors reduce myocardial infarct size in animal models independent of diabetes. Future in vivo studies should focus on clinical translation by exploring whether SGLT2 inhibitors limit infarct size in animals with relevant comorbidities, on top of loading doses of antiplatelet agents. Mechanistic studies should elucidate the potential relationship between the infarct size-lowering effect of SGLT2 inhibitors and the intact organ system. Graphical abstract

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“…We previously showed that left ventricular (LV) SGLT1 is upregulated in patients with end-stage heart failure (HF) compared with non-failing controls [2]. In these patients, SGLT1 expression showed a significant correlation with the extent of LV dilation and systolic dysfunction independent of age, sex, and body mass index [2]. Knockout or knockdown of SGLT1 prevents LV pathological remodeling in murine models of pressure overload [3] or type 2 diabetes mellitus (T2DM) [4,5], whereas humans with functionally limited SGLT1 have substantially lower risk of developing HF in the long-term [6].…”

Section: Introductionmentioning

confidence: 99%

Left Ventricular SGLT1 Protein Expression Correlates with the Extent of Myocardial Nitro-Oxidative Stress in Rats with Pressure and Volume Overload-Induced Heart Failure

et al. 2021

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Myocardial sodium-glucose cotransporter 1 (SGLT1) has been shown to be upregulated in humans with heart failure (HF) with or without diabetes. In vitro studies have linked SGLT1 to increased nitro-oxidative stress in cardiomyocytes. We aimed to assess the relation between left ventricular (LV) SGLT1 expression and the extent of nitro-oxidative stress in two non-diabetic rat models of chronic heart failure (HF) evoked by either pressure (TAC, n = 12) or volume overload (ACF, n = 12). Sham-operated animals (Sham-T and Sham-A, both n = 12) served as controls. Both TAC and ACF induced characteristic LV structural and functional remodeling. Western blotting revealed that LV SGLT1 protein expression was significantly upregulated in both HF models (both p < 0.01), whereas the phosphorylation of ERK1/2 was decreased only in ACF; AMPKα activity was significantly reduced in both models. The protein expression of the Nox4 NADPH oxidase isoform was increased in both TAC and ACF compared with respective controls (both p < 0.01), showing a strong positive correlation with SGLT1 expression (r = 0.855, p < 0.001; and r = 0.798, p = 0.001, respectively). Furthermore, SGLT1 protein expression positively correlated with the extent of myocardial nitro-oxidative stress in failing hearts assessed by 3-nitrotyrosin (r = 0.818, p = 0.006) and 4-hydroxy-2-nonenal (r = 0.733, p = 0.020) immunostaining. Therefore, LV SGLT1 protein expression was upregulated irrespective of the nature of chronic hemodynamic overload, and correlated significantly with the expression of Nox4 and with the level of myocardial nitro-oxidative stress, suggesting a pathophysiological role of SGLT1 in HF.

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Characterization of left ventricular myocardial sodium-glucose cotransporter 1 expression in patients with end-stage heart failure

Cited by 31 publications

References 54 publications

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

Sodium–glucose cotransporter 2 inhibitors reduce myocardial infarct size in preclinical animal models of myocardial ischaemia–reperfusion injury: a meta-analysis

Left Ventricular SGLT1 Protein Expression Correlates with the Extent of Myocardial Nitro-Oxidative Stress in Rats with Pressure and Volume Overload-Induced Heart Failure

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