Role of SGLT1 in high glucose level-induced MMP-2 expression in human cardiac fibroblasts

Meng, Lingjun; Uzui, Hiroyasu; Guo, Hangyuan; Tada, Hiroshi

doi:10.3892/mmr.2018.8688

Cited by 23 publications

(24 citation statements)

References 33 publications

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“…The latter is a shared pathology in HF patients with and without diabetes [8]. In response to high glucose concentrations, SGLT1 contributed to cellular glucotoxicity in cultured rat cardiomyocytes via increased activation of NAPDH-oxidase [45], whereas it facilitated profibrotic signaling in human cardiac fibroblasts [46]. Nonetheless, in the present study, immunohistochemical staining of SGLT1 suggested that cardiomyocytes-but not fibrotic tissue-are the primary sources of SGLT1 expression in the myocardium, in line with Kashiwagi et al [19].…”

Section: Discussionmentioning

confidence: 99%

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

Sayour

Oláh

Ruppert

et al. 2020

Cardiovasc Diabetol

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Background 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. Methods 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. Results 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. Conclusions 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.

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Section: Discussionmentioning

confidence: 99%

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

Sayour

Oláh

Ruppert

et al. 2020

Cardiovasc Diabetol

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“…There may also be some compensatory mechanisms activated in those mouse hearts by the permanent knock-down of cardiac SGLT1 from birth. Considering that the SGLT1 expression is chronically increased under diabetic conditions [19,21], resulting in detrimental effects [21,25,40], it is important to attain the effects of SGLT1 on the cardiac function as well as energy metabolism during acute phase of IRI, particularly in insulin-resistant diabetic models. We found in the present study that, under insulin-resistant conditions, SGLT1 isoform may play a compensatory protective role during the loss of GLUT4-mediated glucose uptake, rather than provides detrimental impacts on the diabetic myocardium [21,25], at least during the acute phase of IRI.…”

Section: Discussionmentioning

confidence: 99%

“…It is also important to assess the expression of those glucose transporters in isolated cardiomyocytes, considering that not only myocardial SGLT1 and other glucose transporters but also those residing in cardiac fibroblasts [40] and endothelial cells [67] may play a substantial role under diverse pathological conditions, such as ischemic heart diseases as well as diabetes (insulin resistant conditions), and the regulation of the expression of those glucose transporters might differ among cell types.…”

Section: Discussionmentioning

confidence: 99%

Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity

Yoshii

Nagoshi

Kashiwagi

et al. 2019

Cardiovasc Diabetol

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Background: Recent large-scale clinical trials have shown that SGLT2-inhibitors reduce cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac sodium-glucose cotransporter (SGLT1 is the dominant isoform) compared with those of other glucose transporters (insulin-dependent GLUT4 is the major isoform) remain incompletely understood. Given that glucose is an important preferential substrate for myocardial energy metabolism under conditions of ischemia-reperfusion injury (IRI), we hypothesized that SGLT1 contributes to cardioprotection during the acute phase of IRI via enhanced glucose transport, particularly in insulin-resistant phenotypes. Methods and results: The hearts from mice fed a high-fat diet (HFD) for 12 weeks or a normal-fat diet (NFD) were perfused with either the non-selective SGLT-inhibitor phlorizin or selective SGLT2-inhibitors (tofogliflozin, ipragliflozin, canagliflozin) during IRI using Langendorff model. After ischemia-reperfusion, HFD impaired left ventricular developed pressure (LVDP) recovery compared with the findings in NFD. Although phlorizin-perfusion impaired LVDP recovery in NFD, a further impaired LVDP recovery and a dramatically increased infarct size were observed in HFD with phlorizin-perfusion. Meanwhile, none of the SGLT2-inhibitors significantly affected cardiac function or myocardial injury after ischemia-reperfusion under either diet condition. The plasma membrane expression of GLUT4 was significantly increased after IRI in NFD but was substantially attenuated in HFD, the latter of which was associated with a significant reduction in myocardial glucose uptake. In contrast, SGLT1 expression at the plasma membrane remained constant during IRI, regardless of the diet condition, whereas SGLT2 was not detected in the hearts of any mice. Of note, phlorizin considerably reduced myocardial glucose uptake after IRI, particularly in HFD. Conclusions: Cardiac SGLT1 but not SGLT2 plays a compensatory protective role during the acute phase of IRI via enhanced glucose uptake, particularly under insulin-resistant conditions, in which IRI-induced GLUT4 upregulation is compromised.

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“…Consistent with this finding, transgenic overexpression of cardiac SGLT1 was associated with myocardial hypertrophy and left ventricular dysfunction that was reversible by SGLT1 suppression. In another study, human cardiac fibroblasts exposed to high glucose levels increased expression of proteins involved in cardiac fibrosis (i.e., matrix metalloproteinase-2) that was reversed by phlorizin (a dual SGLT1 and SGLT2 inhibitor) but not by dapagliflozin (an SGLT2 inhibitor) (31). In addition to our data, these studies provide support for the role of SGLT1 as a cardiac sodium/glucose transporter that may be involved in cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk

Seidelmann

Feofanova

et al. 2018

Journal of the American College of Cardiology

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BACKGROUND Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. OBJECTIVES The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. METHODS Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed. RESULTS Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplo-type of 3 missense mutations (frequency of 6.7%)—Asn51Ser, Ala411Thr, and His615Gln—had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (β-coefficient: −8.0; 95% confidence interval [CI]: −12.7 to −3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (β = −16.3; 95% CI: −36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (β = −3.2; 95% CI: −6.4 to −0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). CONCLUSIONS Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic condition/ns.

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Role of SGLT1 in high glucose level-induced MMP-2 expression in human cardiac fibroblasts

Cited by 23 publications

References 33 publications

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

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

Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity

Genetic Variants in SGLT1, Glucose Tolerance, and Cardiometabolic Risk

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