Restoring mitochondrial biogenesis with metformin attenuates β-GP-induced phenotypic transformation of VSMCs into an osteogenic phenotype via inhibition of PDK4/oxidative stress-mediated apoptosis

Ma, Wen-Qi; Sun, Xuejiao; Wang, Ying; Zhu, Yi; Han, Xi‐Qiong; Liu, Naifeng

doi:10.1016/j.mce.2018.08.012

Cited by 76 publications

(72 citation statements)

References 44 publications

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“…Moreover, cellular phenomena that affect osteoinductive intracellular signaling, via hyperphosphatemia, include autophagy, ER stress, and mitochondrial dysfunction. Eventually, various signaling pathways trigger phosphate-induced osteo-/chondrogenic transdifferentiation of VSMCs, as associated with VC [86][87][88]. These complex and cross-talking mechanisms closely support the postulate that VC is affected by phosphate levels.…”

Section: Vascular Smooth Muscle Cell Phenotypic Differentiation In Himentioning

confidence: 58%

Vascular Calcification—New Insights into Its Mechanism

Lee

Jeon

2020

IJMS

237

254

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Vascular calcification (VC), which is categorized by intimal and medial calcification, depending on the site(s) involved within the vessel, is closely related to cardiovascular disease. Specifically, medial calcification is prevalent in certain medical situations, including chronic kidney disease and diabetes. The past few decades have seen extensive research into VC, revealing that the mechanism of VC is not merely a consequence of a high-phosphorous and -calcium milieu, but also occurs via delicate and well-organized biologic processes, including an imbalance between osteochondrogenic signaling and anticalcific events. In addition to traditionally established osteogenic signaling, dysfunctional calcium homeostasis is prerequisite in the development of VC. Moreover, loss of defensive mechanisms, by microorganelle dysfunction, including hyper-fragmented mitochondria, mitochondrial oxidative stress, defective autophagy or mitophagy, and endoplasmic reticulum (ER) stress, may all contribute to VC. To facilitate the understanding of vascular calcification, across any number of bioscientific disciplines, we provide this review of a detailed updated molecular mechanism of VC. This encompasses a vascular smooth muscle phenotypic of osteogenic differentiation, and multiple signaling pathways of VC induction, including the roles of inflammation and cellular microorganelle genesis.

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Section: Vascular Smooth Muscle Cell Phenotypic Differentiation In Himentioning

confidence: 58%

Vascular Calcification—New Insights into Its Mechanism

Lee

Jeon

2020

IJMS

237

254

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“…Reducing excessive oxidative stress improves the locomotor functional recovery after SCI [60]. One previous study has also demonstrated that metformin restores mitochondrial biogenesis by inhibiting of the PDK4/oxidative stress-mediated apoptosis pathway [61]. Based on these studies, we hypothesized that metformin has an important role in preventing excessive oxidative stress after SCI.…”

Section: Discussionmentioning

confidence: 88%

Metformin Promotes Axon Regeneration after Spinal Cord Injury through Inhibiting Oxidative Stress and Stabilizing Microtubule

Wang

Zheng

Han

et al. 2020

Oxidative Medicine and Cellular Longevity

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Spinal cord injury (SCI) is a devastating disease that may lead to lifelong disability. Thus, seeking for valid drugs that are beneficial to promoting axonal regrowth and elongation after SCI has gained wide attention. Metformin, a glucose-lowering agent, has been demonstrated to play roles in various central nervous system (CNS) disorders. However, the potential protective effect of metformin on nerve regeneration after SCI is still unclear. In this study, we found that the administration of metformin improved functional recovery after SCI through reducing neuronal cell apoptosis and repairing neurites by stabilizing microtubules via PI3K/Akt signaling pathway. Inhibiting the PI3K/Akt pathway with LY294002 partly reversed the therapeutic effects of metformin on SCI in vitro and vivo. Furthermore, metformin treatment weakened the excessive activation of oxidative stress and improved the mitochondrial function by activating the nuclear factor erythroid-related factor 2 (Nrf2) transcription and binding to the antioxidant response element (ARE). Moreover, treatment with Nrf2 inhibitor ML385 partially abolished its antioxidant effect. We also found that the Nrf2 transcription was partially reduced by LY294002 in vitro. Taken together, these results revealed that the role of metformin in nerve regeneration after SCI was probably related to stabilization of microtubules and inhibition of the excessive activation of Akt-mediated Nrf2/ARE pathway-regulated oxidative stress and mitochondrial dysfunction. Overall, our present study suggests that metformin administration may provide a potential therapy for SCI.

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“…Mitochondrial fusion and mitophagy play a pivotal role in the development of VC [6,7]. Optic atrophy 1 (OPA1) is a key regulator of mitochondrial fusion, and the AMP-activated protein kinase (AMPK)/OPA1 pathway is associated with mitochondrial fusion/mitophagy during cardiovascular disease [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…Phosphorylated-AMPK protein levels were shown to be decreased in VC, and ghrelin improved VC through AMPK activation [10]. Metformin was shown to inhibit beta-glycerophosphate-(β-GP-) induced impairment of mitochondrial biogenesis via AMPK activation in VC [6]. Melatonin, the main indoleamine produced by the pineal gland, is known to have anti-inflammatory, anticancer, and antioxidant activities [11].…”

Section: Introductionmentioning

confidence: 99%

Melatonin Attenuates Calcium Deposition from Vascular Smooth Muscle Cells by Activating Mitochondrial Fusion and Mitophagy via an AMPK/OPA1 Signaling Pathway

Chen

Zhou

Yang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Mitochondrial fusion/mitophagy plays a role in cardiovascular calcification. Melatonin has been shown to protect against cardiovascular disease. This study sought to explore whether melatonin attenuates vascular calcification by regulating mitochondrial fusion/mitophagy via the AMP-activated protein kinase/optic atrophy 1 (AMPK/OPA1) signaling pathway. The effects of melatonin on vascular calcification were investigated in vascular smooth muscle cells (VSMCs). Calcium deposits were visualized by Alizarin Red S staining, while calcium content and alkaline phosphatase (ALP) activity were used to evaluate osteogenic differentiation. Western blots were used to measure expression of runt-related transcription factor 2 (Runx2), mitofusin 2 (Mfn2), mito-light chain 3 (mito-LC3) II, and cleaved caspase 3. Melatonin markedly reduced calcium deposition and ALP activity. Runx2 and cleaved caspase 3 were downregulated in response to melatonin, whereas Mfn2 and mito-LC3II were enhanced and accompanied by decreased mitochondrial superoxide levels. Melatonin also maintained mitochondrial function and promoted mitochondrial fusion/mitophagy via the OPA1 pathway. However, OPA1 deletion abolished the protective effects of melatonin on VSMC calcification. Melatonin treatment significantly increased p-AMPK and OPA1 protein expression, whereas treatment with compound C ablated the observed benefits of melatonin treatment. Collectively, our results demonstrate that melatonin protects VSMCs against calcification by promoting mitochondrial fusion/mitophagy via the AMPK/OPA1 pathway.

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Restoring mitochondrial biogenesis with metformin attenuates β-GP-induced phenotypic transformation of VSMCs into an osteogenic phenotype via inhibition of PDK4/oxidative stress-mediated apoptosis

Cited by 76 publications

References 44 publications

Vascular Calcification—New Insights into Its Mechanism

Vascular Calcification—New Insights into Its Mechanism

Metformin Promotes Axon Regeneration after Spinal Cord Injury through Inhibiting Oxidative Stress and Stabilizing Microtubule

Melatonin Attenuates Calcium Deposition from Vascular Smooth Muscle Cells by Activating Mitochondrial Fusion and Mitophagy via an AMPK/OPA1 Signaling Pathway

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