Caloric restriction induces H2O2 formation as a trigger of AMPK-eNOS-NO pathway in obese rats: Role for CAMKII

García‐Prieto, Concha F.; Gil‐Ortega, Marta; Plaza, Adrián; Hernández-Martín, Marina; González-Blázquez, Raquel; Alcalá, Martín; Rodríguez-Rodríguez, Pilar; Viana, Marta; Aránguez, Isabel; Gollasch, Maik; Somoza, Beatriz; Fernández-Alfonso, Marı́a S.

doi:10.1016/j.freeradbiomed.2019.05.016

Cited by 17 publications

(10 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…AICAR, once inside the cell, is phosphorylated by adenosine kinases and is converted to ZMP, an AMP mimetic, which binds the CBS sites in γ-AMPK 18 . On the other hand, 2-DG is a competitive inhibitor of glucose metabolism 14 since it is phosphorylated by hexokinase to DG-PO 4 , which is trapped in the cell unable to undergo further metabolism 6 , 19 .…”

Section: Resultsmentioning

confidence: 99%

“…Endothelial AMPK plays a key role in the regulation of vascular function through the activation of the PI3K-Akt-endothelial nitric oxide synthase (eNOS) pathway and stimulation of nitric oxide (NO) release in endothelial cells 4 – 6 . Obesity leads to AMPK dysregulation and endothelial dysfunction, which is the first step in the progression of cardiovascular disease 7 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK–eNOS–NO pathway

Sanz-Gómez

Aledavood

Beroiz-Salaverri

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

Endothelial adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in the regulation of vascular tone through stimulating nitric oxide (NO) release in endothelial cells. Since obesity leads to endothelial dysfunction and AMPK dysregulation, AMPK activation might be an important strategy to restore vascular function in cardiometabolic alterations. Here, we report the identification of a novel AMPK modulator, the indolic derivative IND6, which shows affinity for AMPKα1β1γ1, the primary AMPK isoform in human EA.Hy926 endothelial cells. IND6 shows inhibitory action of the enzymatic activity in vitro, but increases the levels of p-Thr174AMPK, p-Ser1177eNOS and p-Ser79ACC in EA.Hy926. This paradoxical finding might be explained by the ability of IND6 to act as a mixed-type inhibitor, but also to promote the enzyme activation by adopting two distinct binding modes at the ADaM site. Moreover, functional assays reveal that IND6 increased the eNOS-dependent production of NO and elicited a concentration-dependent vasodilation of endothelium-intact rat aorta due to AMPK and eNOS activation, demonstrating a functional activation of the AMPK–eNOS–NO endothelial pathway. This kinase inhibition profile, combined with the paradoxical AMPK activation in cells and arteries, suggests that these new chemical entities may constitute a valuable starting point for the development of new AMPK modulators with therapeutic potential for the treatment of vascular complications associated with obesity.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK–eNOS–NO pathway

Sanz-Gómez

Aledavood

Beroiz-Salaverri

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the present study, oral treatment with both Ang-(1-7) and A-1317 improved the redox process in the liver by increasing eNOS mRNA gene expression and SOD activity and reducing MDA, carbonylated protein and iNOS mRNA gene expression compared to HF/E rats. However, oral treatment with A-1317 increased eNOS mRNA gene expression and SOD activity also compared to CT/E rats and thus, the increase in the AMPK mRNA gene expression may have favored the eNOS mRNA gene expression and SOD activity (Garcıá-Prieto et al, 2019), which together, may have contributed to the restoration of liver damage observed by normalization of ALT and AST levels that was shown only in the treatment with A-1317.…”

Section: )mentioning

confidence: 93%

The Novel Angiotensin-(1–7) Analog, A-1317, Improves Insulin Resistance by Restoring Pancreatic β-Cell Functionality in Rats With Metabolic Syndrome

Barbosa

Lima

et al. 2020

Front. Pharmacol.

View full text Add to dashboard Cite

In previous studies we have shown that oral Ang-(1–7) has a beneficial therapeutic effect on cardiometabolic disturbances present in metabolic syndrome (MetS). Based on the fact that Ang-(1–7) acts through release of nitric oxide (NO), a new peptide, A-1317 was engineered adding the amino acid L-Arginine, the NO precursor, to the N-terminal portion of the Ang-(1–7). Therefore, in a single molecule the substrate and the activator of NO are combined. In the present study, we evaluated the effect of A-1317 oral treatment on liver-glucose metabolism in MetS induced by high fat (HF) diet in rats. Rats were subjected to control (AIN-93M, CT) or HF diets for 15 weeks to induce MetS and treated with A-1317, Ang-(1–7) included into hydroxypropyl- β -cyclodextrin (HP β CD) or empty HP β CD (E), in the last 7 weeks. At the end of 15 weeks, hemodynamic, biometric, and biochemical parameters, redox process, and qRT-PCR gene expression of NO synthase and RAS components were evaluated in the liver. HF/E rats increased body mass gain, adiposity index, despite the reduction in food intake, increased plasma leptin, total cholesterol, triglycerides, ALT, fasting blood glucose, OGTT and insulin, HOMA-IR and MAP and HR. Furthermore, the MetS rats presented increased in liver angiotensinogen , AT1R , ACE mRNA gene expression and concentration of MDA and carbonylated protein. Both Ang-(1–7) and A-1317 oral treatment in MetS rats reverted most of these alterations. However, A-1317 was more efficient in reducing body mass gain, ALT, AST, total cholesterol, insulin, fasting blood glucose, ameliorating β cell capacity by increasing HOMA- β and QUICKI, whereas Ang-(1–7) reduced HOMA- β and QUICKI. In addition, Ang-(1–7) increased Mas and AKT liver mRNA gene expression, while A-1317 increased both Mas and MRGD and AMPK liver mRNA gene expression, suggesting a distinct pathway of action of Ang-(1–7) and A-1317 in MetS rats. Taken together, our data showed that treatment with A-1317 was able to ameliorate MetS disorders and suggested that this effect was mainly via MRGD via activation of AMPK and increasing β cell function.

show abstract

“…Different studies have demonstrated that AMPK increases eNOS expression in an indirect manner by the phosphatidylinositol-3-kinase-protein/AKT pathway [56,57]. In addition, it has recently been demonstrated by García-Prieto et al that Ca 2+ /calmodulin-dependent kinase II plays a crucial action in mediating CR-induced AMPK activation through H 2 O 2 increase in aortas from obese rats [58]. In addition, AMPK improves NO bioavailability by downregulating NOX4 expression, as demonstrated by studies using different drugs able to active AMPK [59].…”

Section: From Caloric Restriction To Caloric Restriction Mimeticsmentioning

confidence: 97%

Diabetes Mellitus and Cardiovascular Diseases: Nutraceutical Interventions Related to Caloric Restriction

Senesi

Ferrulli

Luzi

et al. 2021

IJMS

View full text Add to dashboard Cite

Type 2 diabetes (T2DM) and cardiovascular disease (CVD) are closely associated and represent a key public health problem worldwide. An excess of adipose tissue, NAFLD, and gut dysbiosis establish a vicious circle that leads to chronic inflammation and oxidative stress. Caloric restriction (CR) is the most promising nutritional approach capable of improving cardiometabolic health. However, adherence to CR represents a barrier to patients and is the primary cause of therapeutic failure. To overcome this problem, many different nutraceutical strategies have been designed. Based on several data that have shown that CR action is mediated by AMPK/SIRT1 activation, several nutraceutical compounds capable of activating AMPK/SIRT1 signaling have been identified. In this review, we summarize recent data on the possible role of berberine, resveratrol, quercetin, and L-carnitine as CR-related nutrients. Additionally, we discuss the limitations related to the use of these nutrients in the management of T2DM and CVD.

show abstract

Caloric restriction induces H2O2 formation as a trigger of AMPK-eNOS-NO pathway in obese rats: Role for CAMKII

Cited by 17 publications

References 69 publications

Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK–eNOS–NO pathway

Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK–eNOS–NO pathway

The Novel Angiotensin-(1–7) Analog, A-1317, Improves Insulin Resistance by Restoring Pancreatic β-Cell Functionality in Rats With Metabolic Syndrome

Diabetes Mellitus and Cardiovascular Diseases: Nutraceutical Interventions Related to Caloric Restriction

Contact Info

Product

Resources

About