Sodium glucose cotransporter 1 (SGLT1) inhibitors in cardiovascular protection: Mechanism progresses and challenges

Li, Yebei; Xu, Gaosi

doi:10.1016/j.phrs.2021.106049

Cited by 10 publications

(4 citation statements)

References 92 publications

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“…In addition, the down-regulation of SGLT1 and PCNA expression was observed in PAH rats treated with CANA. Our results support the association of SGLT1, rather than SGLT2, with cardiovascular disease, aligning with recent research [18,19]. SGLT1 expression was upregulated in the LV of HF patients, regardless of diabetes status [60].…”

Section: Discussionsupporting

confidence: 93%

“…SGLT1 was located on the small intestine brush border membrane, facilitates rapid absorption of glucose and galactose from the gastrointestinal tract [17]. Growing evidence suggested that SGLT1 was closely implicated in the pathological of cardiovascular diseases, including oxidative stress, inflammation, fibrosis, proliferation [18,19]. However, the precise involvement and contribution of SGLT1 and SGLT2 in the proliferation of PASMCs in pulmonary arteries remain uncertain.…”

Section: Introductionmentioning

confidence: 99%

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Canagliflozin inhibits PASMCs proliferation via regulating SGLT1/AMPK signaling and attenuates vascular remodeling in MCT-induced pulmonary arterial hypertension

Chen,

Yu,

Lian

et al. 2023

Preprint

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Background Pulmonary arterial hypertension (PAH) is a progressive, devastating vascular disease that eventually leads to right heart failure (RHF). Recent studies have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) are effective in reducing cardiovascular events in patients with HF, but their efficacy in treating PAH remains uncertain. The aim of this study was to investigate the effects of canagliflozin (CANA), an SGLT2i with mild SGLT1 inhibitory effects, on rats with PAH, as well as its direct impact on pulmonary arterial smooth muscle cells (PASMCs). Methods PAH was induced in rats by subcutaneous injection of monocrotaline (MCT) (40 mg/kg), followed by 4 weeks of treatment with CANA by gavage (30 mg/kg/day) or saline alone. Echocardiography, hemodynamic measurements, and histological staining were performed to evaluate pulmonary vascular and right ventricular (RV) structure and function. The effect of CANA on cell proliferation was further investigated in PASMCs. Platelet-derived growth factor (PDGF)-BB, AMP kinase (AMPK) inhibitor compound C (CC) and siSGLT1 were utilized to explore the molecular regulation mechanism of CANA. Results Pulmonary artery and RV remodeling and dysfunction in PAH were alleviated with CANA, as assessed by echocardiography. Hemodynamic parameters, such as RV systolic pressure, and structural of pulmonary arteriole, including vascular wall thickness and wall area, were reduced by CANA treatment. RV hypertrophy index, cardiomyocyte hypertrophy, and fibrosis were decreased with CANA treatment. In vitro, PASMCs proliferation was inhibited by CANA, regardless of PDGF-BB stimulation. Activation of AMPK was induced by CANA treatment in cultured PASMCs in a time- and concentration-dependent manner. These effects of CANA were attenuated by treatment with CC. Abundant expression of SGLT1 was observed in PASMCs and pulmonary arteries of rats, while SGLT2 expression was undetectable. SGLT1 was increased in response to PDGF-BB stimulation, while PASMCs proliferation was inhibited and beneficial effects of CANA were counteracted by knockdown of SGLT1. Conclusions It is demonstrated for the first time that CANA inhibited the proliferation of PASMCs by regulating SGLT1/AMPK signaling and thus exerted an anti-proliferative effect on MCT-induced PAH. Our research revealed a novel mechanism for the beneficial effects of CANA on pulmonary vasculature.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Canagliflozin inhibits PASMCs proliferation via regulating SGLT1/AMPK signaling and attenuates vascular remodeling in MCT-induced pulmonary arterial hypertension

Chen,

Yu,

Lian

et al. 2023

Preprint

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“…However, SGLT1 inhibitors showed no significant association with CVD. While numerous laboratory studies have demonstrated the potential cardioprotective effects of SGLT1 inhibitors, clinical evidence from large‐scale trials is still lacking to conclusively validate their therapeutic benefits for cardiovascular health (Li & Xu, 2022 ). For CKD, neither SGLT1 nor SGLT2 inhibitors demonstrated a significant association, despite clinical trials showing nephroprotective benefits of SGLT2 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Sodium‐glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: A Mendelian randomization study

Liu,

Shi,

Shao

2024

Brain and Behavior

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IntroductionThis study aims to evaluate the effects of sodium‐glucose cotransporter 1 inhibitors (SGLT1i) and sodium‐glucose cotransporter 2 inhibitors (SGLT2i) on neurodegenerative disorders and to investigate the role of hemoglobin A1c (HbA1c) levels.MethodsUtilizing drug target Mendelian randomization, we employed single nucleotide polymorphisms (SNPs) proximal to the SLC5A1 and SLC5A2 genes to analyze the influence of SGLT1i and SGLT2i on Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), frontotemporal dementia (FTD), Lewy body dementia (LBD), and amyotrophic lateral sclerosis (ALS), with type 2 diabetes (T2D) as a positive control. An additional analysis examined the impact of HbA1c levels on the same disorders.ResultsSGLT1i exhibited a significant association with decreased risk for ALS and MS. Conversely, SGLT2i were linked to an increased risk of AD, PD, and MS. Elevated HbA1c levels, independent of SGLT1 and SGLT2 effects, were associated with an increased risk of PD. Sensitivity analyses supported the robustness of these findings.ConclusionOur study suggests that SGLT1i may confer protection against ALS and MS, whereas SGLT2i could elevate the risk of AD, PD, and MS. Additionally, elevated HbA1c levels emerged as a risk factor for PD. These findings underscore the importance of personalized approaches in the utilization of SGLT inhibitors, considering their varying impacts on the risks of neurodegenerative diseases.

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“…The presence of SGLT1 in the heart is well established and is reportedly overexpressed in T2DM patients [136]. Along with glucose transporters (GLUT), SGLT1 is involved in cardiomyocyte glucose uptake, and in ischemic conditions, SGLT1 is reported to supplement the ATP reserve by increasing glucose utilization, thus playing a role in myocardial energy metabolism [137,138]. Several clinical trials with SGLT2is have emphasized cardiac benefits, but most of these drugs show a variable affinity for SGLT1.…”

Section: Moderate Genital Infectionsmentioning

confidence: 99%

mTORC1 and SGLT2 Inhibitors—A Therapeutic Perspective for Diabetic Cardiomyopathy

Saha,

Fang,

Green

et al. 2023

IJMS

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Diabetic cardiomyopathy is a critical diabetes-mediated co-morbidity characterized by cardiac dysfunction and heart failure, without predisposing hypertensive or atherosclerotic conditions. Metabolic insulin resistance, promoting hyperglycemia and hyperlipidemia, is the primary cause of diabetes-related disorders, but ambiguous tissue-specific insulin sensitivity has shed light on the importance of identifying a unified target paradigm for both the glycemic and non-glycemic context of type 2 diabetes (T2D). Several studies have indicated hyperactivation of the mammalian target of rapamycin (mTOR), specifically complex 1 (mTORC1), as a critical mediator of T2D pathophysiology by promoting insulin resistance, hyperlipidemia, inflammation, vasoconstriction, and stress. Moreover, mTORC1 inhibitors like rapamycin and their analogs have shown significant benefits in diabetes and related cardiac dysfunction. Recently, FDA-approved anti-hyperglycemic sodium–glucose co-transporter 2 inhibitors (SGLT2is) have gained therapeutic popularity for T2D and diabetic cardiomyopathy, even acknowledging the absence of SGLT2 channels in the heart. Recent studies have proposed SGLT2-independent drug mechanisms to ascertain their cardioprotective benefits by regulating sodium homeostasis and mimicking energy deprivation. In this review, we systematically discuss the role of mTORC1 as a unified, eminent target to treat T2D-mediated cardiac dysfunction and scrutinize whether SGLT2is can target mTORC1 signaling to benefit patients with diabetic cardiomyopathy. Further studies are warranted to establish the underlying cardioprotective mechanisms of SGLT2is under diabetic conditions, with selective inhibition of cardiac mTORC1 but the concomitant activation of mTORC2 (mTOR complex 2) signaling.

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Sodium glucose cotransporter 1 (SGLT1) inhibitors in cardiovascular protection: Mechanism progresses and challenges

Cited by 10 publications

References 92 publications

Canagliflozin inhibits PASMCs proliferation via regulating SGLT1/AMPK signaling and attenuates vascular remodeling in MCT-induced pulmonary arterial hypertension

Canagliflozin inhibits PASMCs proliferation via regulating SGLT1/AMPK signaling and attenuates vascular remodeling in MCT-induced pulmonary arterial hypertension

Sodium‐glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: A Mendelian randomization study

mTORC1 and SGLT2 Inhibitors—A Therapeutic Perspective for Diabetic Cardiomyopathy

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