Inhibition of SGLT1 protects against glycemic variability-induced cardiac damage and pyroptosis of cardiomyocytes in diabetic mice

Sun, Zhi; Chai, Qian; Zhang, Ziying; Lu, Dexue; Meng, Ziang; Wu, Weihua

doi:10.1016/j.lfs.2021.119116

Cited by 15 publications

(14 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with data on human hearts, myocardial SGLT1 mRNA or protein expression was found to be upregulated in non-diabetic small animal models of acute myocardial ischemia-reperfusion injury [55] or ischemic preconditioning [56], permanent LAD ligation (model of ICM) [51,57,58], and hemodynamic-overload induced HF [59,60], as well as in models of metabolic syndrome and T2DM [51,54,[61][62][63][64]. Interestingly, SGLT1 was downregulated in mice with streptozotocin-induced type 1 diabetes mellitus (T1DM) [51].…”

Section: Changes In Expression Of Sglt1 In Various Myocardial Disease Statessupporting

confidence: 59%

Effects of SGLT2 Inhibitors beyond Glycemic Control—Focus on Myocardial SGLT1

Sayour

Ruppert

Oláh

et al. 2021

IJMS

View full text Add to dashboard Cite

Selective sodium–glucose cotransporter 2 (SGLT2) inhibitors reduced the risk of hospitalization for heart failure in patients with or without type 2 diabetes (T2DM) in large-scale clinical trials. The exact mechanism of action is currently unclear. The dual SGLT1/2 inhibitor sotagliflozin not only reduced hospitalization for HF in patients with T2DM, but also lowered the risk of myocardial infarction and stroke, suggesting a possible additional benefit related to SGLT1 inhibition. In fact, several preclinical studies suggest that SGLT1 plays an important role in cardiac pathophysiological processes. In this review, our aim is to establish the clinical significance of myocardial SGLT1 inhibition through reviewing basic research studies in the context of SGLT2 inhibitor trials.

show abstract

Section: Changes In Expression Of Sglt1 In Various Myocardial Disease Statessupporting

confidence: 59%

Effects of SGLT2 Inhibitors beyond Glycemic Control—Focus on Myocardial SGLT1

Sayour

Ruppert

Oláh

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…In these patients, LV SGLT1 expression was independently associated with the extent of LV dilation and systolic dysfunction [ 2 ], highlighting the clinical relevance of upregulation of LV SGLT1 in HF. Similarly, previous studies noted that SGLT1 expression was upregulated in non-diabetic small animal models of acute myocardial ischemia-reperfusion injury [ 7 ], and permanent left anterior descending coronary artery ligation (model of ischemic heart disease) [ 1 , 31 ], as well as in models of metabolic syndrome/T2DM [ 1 , 4 , 5 , 30 ]. Matsushita et al [ 3 ] reported that in non-diabetic mice with pressure overload (TAC) for 6 weeks, LV mRNA expression of SGLT1 was significantly upregulated, together with those of the pathological markers CTGF and Col1a1.…”

Section: Discussionmentioning

confidence: 56%

“…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 ]. These suggest that SGLT1 is causally implicated in the development of HF.…”

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

View full text Add to dashboard Cite

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.

show abstract

“…Targeting SGLT1 has also been found to have cardioprotective effects in DCM. RNA-mediated inhibition of SGLT1 gene glycemic variability and cardiac damage were seen in type 2 diabetes mellitus mice in vivo ( Sun et al, 2021 ). In cultured cardiomyocytes, SGLT1 knockdown restored cell proliferation, suppressed reactive oxygen species, and induced cytotoxicity ( Chai et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

Inhibition of SGLT1 protects against glycemic variability-induced cardiac damage and pyroptosis of cardiomyocytes in diabetic mice

Cited by 15 publications

References 41 publications

Effects of SGLT2 Inhibitors beyond Glycemic Control—Focus on Myocardial SGLT1

Effects of SGLT2 Inhibitors beyond Glycemic Control—Focus on Myocardial SGLT1

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

SGLT1 Knockdown Attenuates Cardiac Fibroblast Activation in Diabetic Cardiac Fibrosis

Contact Info

Product

Resources

About