G004, a synthetic sulfonylurea compound, exerts anti-atherosclerosis effects by targeting SIRT1 in ApoE −/− mice

Qian, Lifen; Ma, Lingman; Wu, Guanzhong; Q, Yu; Lin, Hui-Sheng; Ying, Qidi; Wen, Dan; Gao, Cong

doi:10.1016/j.vph.2016.12.003

Cited by 15 publications

(10 citation statements)

References 46 publications

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“…However, research on sirtuinmodulating compounds is still intensive, and specific hydrophobic motifs found in SIRT1 substrates, such as FOXO3a and PGC-1a, seem to facilitate SIRT1 activation by sirtuinactivating compounds (STACs) acting through a mechanism of direct ''assisted allosteric activation'' mediated by an N-terminal activation domain in SIRT1 (74,75,148). Moreover, recently, a synthetic sulfonylurea compound (G004) showed beneficial effects on ApoE -/-mice against hyperglycemia and atherosclerosis by acting on SIRT1/ eNOS axis (149), and a novel PARP1 inhibitor AG-690/ 11026014 showed protective effects on Ang II-induced mouse cardiac remodeling by restoring the activity of SIRT1 in heart tissues (54).…”

Section: Sirt1 and Sirt6 Pharmacological Modulators In The Preclinicamentioning

confidence: 99%

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

D’Onofrio¹,

Servillo²,

Balestrieri³

2018

Antioxidants & Redox Signaling

296

238

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Significance: Oxidative stress represents the common hallmark of pathological conditions associated with cardiovascular disease (CVD), including atherosclerosis, heart failure, hypertension, aging, diabetes, and other vascular system-related diseases. The sirtuin (SIRT) family, comprising seven proteins (SIRT1-SIRT7) sharing a highly conserved nicotinamide adenine dinucleotide (NAD + )-binding catalytic domain, attracted a great attention for the past few years as stress adaptor and epigenetic enzymes involved in the cellular events controlling aging-related disorder, cancer, and CVD. Recent Advances: Among sirtuins, SIRT1 and SIRT6 are the best characterized for their protective roles against inflammation, vascular aging, heart disease, and atherosclerotic plaque development. This latest role has been only recently unveiled for SIRT6. Of interest, in recent years, complex signaling networks controlled by SIRT1 and SIRT6 common to stress resistance, vascular aging, and CVD have emerged. Critical Issues: We provide a comprehensive overview of recent developments on the molecular signaling pathways controlled by SIRT1 and SIRT6, two post-translational modifiers proven to be valuable tools to dampen inflammation and oxidative stress at the cardiovascular level. Future Directions: A deeper understanding of the epigenetic mechanisms through which SIRT1 and SIRT6 act in the signalings responsible for onset and development CVD is a prime scientific endeavor of the upcoming years. Multiple ''omic'' technologies will have widespread implications in understanding such mechanisms, speeding up the achievement of selective and efficient pharmacological modulation of sirtuins for future applications in the prevention and treatment of CVD. Antioxid. Redox Signal. 28, 711-732.

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Section: Sirt1 and Sirt6 Pharmacological Modulators In The Preclinicamentioning

confidence: 99%

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

D’Onofrio¹,

Servillo²,

Balestrieri³

2018

Antioxidants & Redox Signaling

296

238

View full text Add to dashboard Cite

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“…Sirt1, a highly conserved NAD + -dependent histone deacetylase, is a vital protein and target for pathways involved in the regulation of lifespan and aging-related diseases [ 24 ]. Sirt1 has been shown to be atheroprotective in apoE –/– mice [ 25 , 26 ]. Recent studies have shown that Sirt1 also plays an important role in the pathogenesis of osteoporosis, as well as in mesenchymal stem cell differentiation [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin promotes bone formation in aged apoE–/– mice through the Sirt1–Runx2 axis

et al. 2020

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Background: Statins are the most widely used drugs in elderly patients; the most common clinical application of statins is in aged hyperlipemia patients. There are few studies on the effects and mechanisms of statins on bone in elderly mice with hyperlipemia. The study is to examine the effects of atorvastatin on bone phenotypes and metabolism in aged apolipoprotein E-deficient (apoE-/-) mice, and the possible mechanisms involved in these changes. Methods: Twenty-four 60-week-old apoE-/mice were randomly allocated to two groups. Twelve mice were orally gavaged with atorvastatin (10 mg/kg body weight/day) for 12 weeks; the others served as the control group. Bone mass and skeletal microarchitecture were determined using micro-CT. Bone metabolism was assessed by serum analyses, qRT-PCR, and Western blot. Bone marrow-derived mesenchymal stem cells (BMSCs) from apoE-/mice were differentiated into osteoblasts and treated with atorvastatin and silent information regulator 1 (Sirt1) inhibitor EX-527. Results: The results showed that long-term administration of atorvastatin increases bone mass and improves bone microarchitecture in trabecular bone but not in cortical bone. Furthermore, the serum bone formation marker osteocalcin (OCN) was ameliorated by atorvastatin, whereas the bone resorption marker tartrate-resistant acid phosphatase 5b (Trap5b) did not appear obviously changes after the treatment of atorvastatin. The mRNA expression of Sirt1, runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and OCN in bone tissue were increased after atorvastatin administration. Western blot showed same trend in Sirt1 and Runx2. The in vitro study showed that when BMSCs from apoE-/mice were pretreated with EX527, the higher expression of Runx2, ALP, and OCN activated by atorvastatin decreased significantly or showed no difference compared with the control. The protein expression of Runx2 showed same trend. Conclusions: Accordingly, the current study validates the hypothesis that atorvastatin can increase bone mass and promote osteogenesis in aged apoE −/− mice by regulating the Sirt1-Runx2 axis.

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“…Sirt1, a highly conserved NAD + -dependent histone deacetylase, is a vital protein and target for pathways involved in the regulation of lifespan and ageing-related diseases [24]. Sirt1 has been shown to be atheroprotective in apoE -/mice [25,26]. Recent studies have shown that Sirt1 also plays an important role in the pathogenesis of osteoporosis, as well as in mesenchymal stem cell differentiation [27,28].…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin Promotes Bone Formation in Aged apoE–/– Mice through the Sirt1–Runx2 Axis

Hong

Wei

Qiu

et al. 2020

Preprint

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Background: Statins are the most widely used drugs in elderly patients, the most common clinical application of statins is in aged hyperlipemia patients. There are few studies on the effects and mechanisms of statins on bone in elderly mice with hyperlipemia. The study is to examine the effects of atorvastatin on bone phenotypes and metabolism in aged apolipoprotein E-deficient (apoE–/–) mice, and the possible mechanisms involved in these changes. Methods: Twenty-four 60-week-old apoE–/– mice were randomly allocated to two groups. Twelve mice were orally gavaged with atorvastatin (10 mg/kg body weight/day) for 12 weeks; the others served as the control group. Bone mass and skeletal microarchitecture were determined using micro-CT. Bone metabolism was assessed by serum analyses, qRT-PCR, and Western blot. Bone marrow-derived mesenchymal stem cells (BMSCs) from apoE–/– mice were differentiated into osteoblasts and treated with atorvastatin and Sirt1 inhibitor EX-527. Results: The results showed that long-term administration of atorvastatin increases bone mass and improves bone microarchitecture in trabecular bone but not in cortical bone. Furthermore, the serum bone formation marker osteocalcin (OCN) was ameliorated by atorvastatin, whereas the bone resorption marker tartrate-resistant acid phosphatase 5b (Trap5b) did not appear obviously changes after the treatment of atorvastatin. The mRNA expression of Sirt1, runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and OCN in bone tissue were increased after atorvastatin administration. Western blot showed same trend in Sirt1 and Runx2. The in vitro study showed that when BMSCs from apoE–/– mice were pretreated with EX527, the higher expression of Runx2, ALP and OCN activated by atorvastatin decreased significantly or showed no difference compared with the control. The protein expression of Runx2 showed same trend. Conclusions: Accordingly, the current study validates the hypothesis that atorvastatin can increase bone mass and promote osteogenesis in aged apoE−/− mice by regulating the Sirt1–Runx2 axis.

show abstract

G004, a synthetic sulfonylurea compound, exerts anti-atherosclerosis effects by targeting SIRT1 in ApoE −/− mice

Cited by 15 publications

References 46 publications

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

Atorvastatin promotes bone formation in aged apoE–/– mice through the Sirt1–Runx2 axis

Atorvastatin Promotes Bone Formation in Aged apoE–/– Mice through the Sirt1–Runx2 Axis

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