Aicar treatment reduces interstitial fibrosis in aging mice

Cieslik, Katarzyna A.; Trial, JoAnn; Entman, Mark L.

doi:10.1016/j.yjmcc.2017.08.003

Cited by 24 publications

(17 citation statements)

References 15 publications

(28 reference statements)

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“…This is thought to occur in response to inflammation that facilitates natural repair of the endometrium (Gnainsky et al 2015). Through conditional mutagenesis studies or pharmacological activation, AMPK has been shown to reduce fibrosis and/or failure of scars to mature following injury in the liver (Ramezani-Moghadam et al 2015, Liang et al 2017, heart (Hermida et al 2013, Noppe et al 2014, lung (King et al 2012, Sato et al 2016, Tao et al 2017, kidney (Kim et al 2015, Thakur et al 2015, intestine (Cieslik et al 2017), peritoneum (Shin et al 2017, Zheng et al 2017, and adipose (Luo et al 2016). Our findings place AMPK at the center of the unique regenerative process within the endometrium that is essential for maintenance of fertility in the female.…”

Section: Discussionmentioning

confidence: 99%

A functional role for AMPK in female fertility and endometrial regeneration

et al. 2018

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Adenosine monophosphate-activated protein kinase (AMPK) is a highly conserved heterotrimeric complex that acts as an intracellular energy sensor. Based on recent observations of AMPK expression in all structures of the female reproductive system, we hypothesized that AMPK is functionally required for maintaining fertility in the female. This hypothesis was tested by conditionally ablating the two catalytic alpha subunits of AMPK, Prkaa1 and Prkaa2, using Pgr-cre mice. After confirming the presence of PRKAA1, PRKAA2 and the active phospho-PRKAA1/2 in the gravid uterus by immunohistochemistry, control (Prkaa1/2 fl/fl ) and double conditional knockout mice (Prkaa1/2 d/d ) were placed into a six-month breeding trial. While the first litter size was comparable between Prkaa1/2 fl/fl and Prkaa1/2 d/d female mice (P = 0.8619), the size of all subsequent litters was dramatically reduced in Prkaa1/2 d/d female mice (P = 0.0015). All Prkaa1/2 d/d female mice experienced premature reproductive senescence or dystocia by the fourth parity. This phenotype manifested despite no difference in estrous cycle length, ovarian histology in young and old nulliparous or multiparous animals, mid-gestation serum progesterone levels or uterine expression of Esr1 or Pgr between Prkaa1/2 fl/fl and Prkaa1/2 d/d female mice suggesting that the hypothalamic–pituitary–ovary axis remained unaffected by PRKAA1/2 deficiency. However, an evaluation of uterine histology from multiparous animals identified extensive endometrial fibrosis and disorganized stromal-glandular architecture indicative of endometritis, a condition that causes subfertility or infertility in most mammals. Interestingly, Prkaa1/2 d/d female mice failed to undergo artificial decidualization. Collectively, these findings suggest that AMPK plays an essential role in endometrial regeneration following parturition and tissue remodeling that accompanies decidualization.

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Section: Discussionmentioning

confidence: 99%

A functional role for AMPK in female fertility and endometrial regeneration

et al. 2018

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“…Interestingly, the number of mesenchymal fibroblasts is also reduced. Mechanically, AICAR-mediated AMPK activation inhibits the deposition of ECM and fibrosis in aging heart [57]. Aging promotes cardiac inflammation, the effect was attenuated by migration inhibitory factor (MIF) knockout.…”

Section: Inflammationmentioning

confidence: 99%

Targeting AMP-Activated Protein Kinase in Aging-Related Cardiovascular Diseases

Tian¹,

Ma²,

Yin³

et al. 2020

Aging and disease

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Aging is a pivotal risk factor for developing cardiovascular diseases (CVD) due to the lifelong exposure to various risk factors that may affect the heart and vasculature during aging. AMP-activated protein kinase (AMPK), a serine/threonine protein kinase, is a pivotal endogenous energy regulator that protects against various pathological alterations. In this report, we first introduced the protective mechanisms of AMPK signaling in myocardium, such as oxidative stress, apoptosis, inflammation, autophagy and inflammatory response. Next, we introduced the potential correlation between AMPK and cardiac aging. Then, we highlighted the roles of AMPK signaling in cardiovascular diseases, including myocardial ischemia, cardiomyopathy, and heart failure. Lastly, some potential directions and further perspectives were expanded. The information extends our understanding on the protective roles of AMPK in myocardial aging, which may contribute to the design of drug targets and sheds light on potential treatments of AMPK for aging-related CVD.

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“…AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside) is an agonist of the AMPK pathway. Previous studies showed that AICAR treatment reduced tubulointerstitial and interstitial fibrosis [11, 12]. In this study, we aimed to determine whether AICAR could ameliorate portal hypertension in an animal model.…”

Section: Introductionmentioning

confidence: 99%

AMPK agonist AICAR ameliorates portal hypertension and liver cirrhosis via NO pathway in the BDL rat model

Dong

et al. 2019

J Mol Med

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Recent studies have indicated that the Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK) pathway is closely involved in liver fibrosis and other fibrotic diseases. However, whether targeting the AMPK pathway can rescue liver fibrosis and its complications, such as portal hypertension, is unknown. This study aimed to explore the therapeutic value of AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside), an agonist of the AMPK pathway, on liver fibrosis and portal hypertension in bile duct ligation (BDL) rats. In vitro experiments showed that the gene expression levels of TGF-b, a-SMA, and collagen 1 in primary rat hepatic stellate cells (HSCs) were significantly decreased after AICAR treatment. The p-eNOS expression and nitric oxide (NO) production were increased by AICAR administration in sinusoidal endothelial cells (SECs). For in vivo animal studies, AICAR acutely decreased portal pressure in the BDL and CCL4 fibrotic rats, but not in the partial portal vein ligation (PVL) rats, without changes in systemic hemodynamics. It was also observed by using intravital fluorescence microscopy that AICAR led to sinusoidal vasodilation in situ experiment. We propose that the relevant mechanisms may be related to the activation of the AMPK/NO pathway in SECs and that this activation promoted NO production in the liver, thereby promoting hepatic sinusoid microcirculation and decreased intrahepatic resistance. The results were verified using the NO inhibitor L-NAME. Chronic AICAR treatment also showed profound beneficial effects on the BDL model rats. The hemodynamic condition was greatly improved, but the positive effect could be partially blocked by L-NAME. Moreover, AICAR also decreased hepatic fibrogenesis in the BDL rats. Key messages Acute and chronic use of AICAR could alleviate portal pressure without changing systemic hemodynamics. AICAR induced sinusoidal vasodilation by improving NO bioavailability and ameliorating endothelial dysfunction in vivo and in vitro. AICAR could alleviate liver cirrhosis in the BDL model rats. Electronic supplementary material The online version of this article (10.1007/s00109-019-01746-4) contains supplementary material, which is available to authorized users.

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Aicar treatment reduces interstitial fibrosis in aging mice

Cited by 24 publications

References 15 publications

A functional role for AMPK in female fertility and endometrial regeneration

A functional role for AMPK in female fertility and endometrial regeneration

Targeting AMP-Activated Protein Kinase in Aging-Related Cardiovascular Diseases

AMPK agonist AICAR ameliorates portal hypertension and liver cirrhosis via NO pathway in the BDL rat model

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