Dapagliflozin improves endothelial cell dysfunction by regulating mitochondrial production via the SIRT1/PGC-1α pathway in obese mice

He, Lianqi; Li, Yanhua; Zhang, Di; Song, Hongjie; Xu, Dianguo; Song, Zhanchun

doi:10.1016/j.bbrc.2022.05.022

Cited by 15 publications

(11 citation statements)

References 32 publications

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“…Furthermore, Chen et al reported that AMPK promoted mitochondrial biogenesis by upregulating the activity of peroxisome proliferator-activated receptor c coactivator 1α (PGC1α), which could critically regulate mitochondrial biogenesis . Equally important, deacetylation of PGC-1α by SIRT1 could advance the transcription of mitochondrial genes and enhance mitochondrial functioning . More importantly, Gentric et al found that the PML-PGC1α-dependent mechanism is associated with high-oxidative phosphorylation (OXPHOS) induced by ferroptosis in human ovarian cancers .…”

Section: Discussionmentioning

confidence: 99%

“…53 Equally important, deacetylation of PGC-1α by SIRT1 could advance the transcription of mitochondrial genes and enhance mitochondrial functioning. 54 More importantly, Gentric et human ovarian cancers. 55 Therefore, the AMPK/SIRT1 pathway may upregulate the activity of PGC1α to alleviate mitochondrial dysfunction and HG-induced ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

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A Novel Anti-Osteoporosis Mechanism of VK2: Interfering with Ferroptosis via AMPK/SIRT1 Pathway in Type 2 Diabetic Osteoporosis

Jin

Tan

Yao

et al. 2023

J. Agric. Food Chem.

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Type 2 diabetic osteoporosis (T2DOP) is a chronic bone metabolic disease. Compared with traditional menopausal osteoporosis, the long-term high glucose (HG) microenvironment increases patients’ risk of fracture and osteonecrosis. We were accumulating evidence that implicated ferroptosis as a pivotal mechanism of glucolipotoxicity-mediated death of osteocytes and osteoblast, a novel form of programmed cell death resulting from uncontrolled lipid peroxidation depending on iron. Vitamin K2 (VK2), a fat-soluble vitamin, is clinically applied to prevent osteoporosis and improve coagulation. This study aimed to clarify the role and mechanism of VK2 in HG-mediated ferroptosis. We established the mouse T2DOP model by intraperitoneal injection of streptozotocin solution and a high-fat and high-sugar diet. We also cultured bone marrow mesenchymal stem cells (BMSCs) in HG to simulate the diabetic environment in vitro. Based on our data, VK2 inhibited HG-mediated bone loss and ferroptosis, the latter manifested by decreased levels of mitochondrial reactive oxygen species, lipid peroxidation, and malondialdehyde and increased glutathione in vitro. In addition, VK2 treatment was capable of restoring bone mass and strengthening the expression of SIRT1, GPX4, and osteogenic markers in the distal femurs. As for further mechanism exploration, we found that VK2 could activate AMPK/SIRT1 signaling, and knockdown of SIRT1 by siRNA prevented the VK2-mediated positive effect in HG-cultured BMSCs. Summarily, VK2 could ameliorate T2DOP through the activation of the AMPK/SIRT1 signaling pathway to inhibit ferroptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Novel Anti-Osteoporosis Mechanism of VK2: Interfering with Ferroptosis via AMPK/SIRT1 Pathway in Type 2 Diabetic Osteoporosis

Jin

Tan

Yao

et al. 2023

J. Agric. Food Chem.

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“…At the molecular levels, DAPA administration prevented reperfusion-induced Drp1/Mff upregulation and reversed the levels of Opa1/Mfn2, leading into decreased formation of fragmented mitochondria. The regulatory mechanism of DAPA on mitochondrial fission/fusion is likely associated with Sirt1 or AMPK based on recent in-depth studies 66 , 67 . It has been also found that DAPA reduced reperfusion-caused myocardial injury through improving mitochondrial function, biogenesis and dynamics 68 , suggesting that mitochondria are the downstream target of DAPA.…”

Section: Discussionmentioning

confidence: 99%

SGLT2 inhibitor dapagliflozin reduces endothelial dysfunction and microvascular damage during cardiac ischemia/reperfusion injury through normalizing the XO-SERCA2-CaMKII-coffilin pathways

Ma¹,

Zou²,

Shi³

et al. 2022

Theranostics

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Background: Given the importance of microvascular injury in infarct formation and expansion, development of therapeutic strategies for microvascular protection against myocardial ischemia/reperfusion injury (IRI) is of great interest. Here, we explored the molecular mechanisms underlying the protective effects of the SGLT2 inhibitor dapagliflozin (DAPA) against cardiac microvascular dysfunction mediated by IRI. Methods: DAPA effects were evaluated both in vivo , in mice subjected to IRI, and in vitro , in human coronary artery endothelial cells (HCAECs) exposed to hypoxia/reoxygenation (H/R). DAPA pretreatment attenuated luminal stenosis, endothelial swelling, and inflammation in cardiac microvessels of IRI-treated mice. Results: In H/R-challenged HCAECs, DAPA treatment improved endothelial barrier function, endothelial nitric oxide synthase (eNOS) activity, and angiogenic capacity, and inhibited H/R-induced apoptosis by preventing cofilin-dependent F-actin depolymerization and cytoskeletal degradation. Inhibition of H/R-induced xanthine oxidase (XO) activation and upregulation, sarco(endo)plasmic reticulum calcium-ATPase 2 (SERCA2) oxidation and inactivation, and cytoplasmic calcium overload was further observed in DAPA-treated HCAECs. DAPA also suppressed calcium/Calmodulin (CaM)-dependent kinase II (CaMKII) activation and cofilin phosphorylation, and preserved cytoskeleton integrity and endothelial cell viability following H/R. Importantly, the beneficial effects of DAPA on cardiac microvascular integrity and endothelial cell survival were largely prevented in IRI-treated SERCA2-knockout mice. Conclusions: These results indicate that DAPA effectively reduces cardiac microvascular damage and endothelial dysfunction during IRI through inhibition of the XO-SERCA2-CaMKII-cofilin pathway.

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“…The low PGC-1 α levels were also significantly increased by the SGLT2 inhibitors empagliflozin and canagliflozin in the cardiomyocytes and adipocytes of high-fat diet/streptozotocin-induced diabetic mice and rats [ 50 – 53 ], which was consistent with the effect of SGLT2 inhibitors to reverse hyperglycemia-induced downregulation of PGC-1 α expression in the kidney. Furthermore, in obese mice, the SGLT2 inhibitor dapagliflozin increased endothelial PGC-1 expression and mitochondrial biosynthesis [ 54 ]. In vitro experiments using high glucose- or palmitic acid-induced human umbilical vein endothelial cells revealed that the SGLT2 inhibitor dapagliflozin boosted PGC-1 α expression and reduced ROS [ 54 , 55 ].…”

Section: The Protective Role Of Pgc-1 α In Diabete...mentioning

confidence: 99%

“…Furthermore, in obese mice, the SGLT2 inhibitor dapagliflozin increased endothelial PGC-1 expression and mitochondrial biosynthesis [ 54 ]. In vitro experiments using high glucose- or palmitic acid-induced human umbilical vein endothelial cells revealed that the SGLT2 inhibitor dapagliflozin boosted PGC-1 α expression and reduced ROS [ 54 , 55 ]. All of these findings point to the possibility that SGLT2 inhibitors promote PGC-1 α expression and activity, which in turn might boost mitochondrial biogenesis and ATP production to protect diabetic nephropathy.…”

Section: The Protective Role Of Pgc-1 α In Diabete...mentioning

confidence: 99%

Emerging Protective Actions of PGC-1α in Diabetic Nephropathy

She

Wang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Renal impairment is affected by various mechanisms of oxidative stress, mitochondrial dysfunction, and basement membrane thickening, which are the major causes of renal dysfunction in diabetes. Of note, hyperglycemia-induced mitochondrial dysfunction has been identified as a common cause of diabetic nephropathy and renal impairment, and the decrease in PGC-1α expression brought on by hyperglycemia plays an immensurable role in both the reduction of mitochondrial biogenesis and the rise in oxidative stress. Reduced PGC-1α expression levels may occur with rising SGLT2-dependent increase of cytoplasmic sodium and protons in the renal cells of diabetes, even if the precise mechanism of hyperglycemia-induced disruption of PGC-1α expression has not been identified. Additionally, it has been observed that SGLT2 inhibitors enhance PGC-1α expression and activity and decrease cytoplasmic sodium and protons in many kidney cells, which may be helpful in reducing renal impairment brought on by diabetes. This review summarizes our and other recent studies on the function of PGC-1α in diabetic nephropathy, provides another potential mediator of the lower PGC-1α expression levels brought on by hyperglycemia in diabetics, and identifies a new pathogenesis of diabetes-related renal impairment. It also explains the mechanism underlying the protective effects of SGLT2 inhibitors on diabetic nephropathy. Therefore, it should be taken into account that SGLT2 inhibitors are an effective therapeutic strategy for reducing renal dysfunction caused by diabetes.

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Dapagliflozin improves endothelial cell dysfunction by regulating mitochondrial production via the SIRT1/PGC-1α pathway in obese mice

Cited by 15 publications

References 32 publications

A Novel Anti-Osteoporosis Mechanism of VK2: Interfering with Ferroptosis via AMPK/SIRT1 Pathway in Type 2 Diabetic Osteoporosis

A Novel Anti-Osteoporosis Mechanism of VK2: Interfering with Ferroptosis via AMPK/SIRT1 Pathway in Type 2 Diabetic Osteoporosis

SGLT2 inhibitor dapagliflozin reduces endothelial dysfunction and microvascular damage during cardiac ischemia/reperfusion injury through normalizing the XO-SERCA2-CaMKII-coffilin pathways

Emerging Protective Actions of PGC-1α in Diabetic Nephropathy

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