Introduction: Premenopausal women, as well as females in animal studies, have a reduced risk of cardiovascular diseases and a reduced myocardial susceptibility to ischemia/reperfusion (I/R) injury. However, with constantly increasing prevalence of obesity, the impact of diet-induced obesity on females remains unclear. Mechanisms of autophagy and mitophagy, differentially regulated between males and females, have been shown to be cardioprotective and impacted under nutritional overload. Hypothesis: Autophagy and mitophagy pathways can be involved in both female cardio protection and deleterious effect of obesity. Methods: Male and female C57Bl/6J mice (n =20 per group) of 8 weeks old were fed a low-fat (LFD, 10% fat) or high-fat (HFD, 60% fat) diet for 12 weeks. At 12 weeks, hearts from mice were studied under basal conditions and after global no-flow ischemia and reperfusion on a Langendorff perfusion system. Results: In both males and females, HFD significantly increases body weight (31.4g vs 48.3g and 22.1g vs 39.9g respectively), fat mass (+200% in males and +300% in females) and blood glucose (+79mg/dl and + 54mg/dl, respectively) (all p<0.01). HFD tends to decrease flow reperfusion after global no-flow ischemia and to increase infarct size (p=0.08 in female and p=0.1 in male, n=5) in both sexes. In males and females, HFD increases pSer757-Ulk1 and decreases Parkin levels under basal conditions (all p<0.006). Moreover, HFD tends to decrease pThr172-AMPK only in females. After I/R, Parkin levels remain lower in HFD groups without sex-difference (p<0.004) but a drastic increase of LC3-II occurs only in females under HFD (p=0.047). Conclusion: All together, these results suggest an impairment of autophagy and mitophagy pathways under HFD. A more drastic change occurs in female mice and may imply a more important response of female mice to HFD, although further studies are needed. However, this result suggests that cardiovascular disease may be more deleterious in women despite their lower cardiovascular risk; additional studies examining sex differences in the response to metabolic syndrome and ischemic heart disease are warranted.
Mitophagy plays a major role in heart physiology. Impairment of Parkin-dependent mitophagy in heart is known to be deleterious. Obesity is a known cardiovascular risk factor. Impaired autophagy has been reported in models of obesity or hyperlipidemia/hypercholesterolemia; however less is known regarding obesity and mitophagy. The aim of this study was to evaluate the regulation of Parkin expression in hearts of mice fed a high fat diet. Interestingly, we found a significant decrease in Parkin protein in hearts of HFD mice compared those fed a low-fat diet. This was associated with mitochondrial dysfunction in the context of ischemia/reperfusion (I/R). This downregulation was not associated with a decrease in Parkin mRNA expression. We did not detect any change in the degradation rate of Parkin and only a slight decrease in its translation. The reduction of Parkin protein abundance in HFD hearts remains a mystery and will need further studies. However, Parkin depletion in the setting of obesity may contribute to cardiovascular risk.
Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through AKT proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations' occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA (n = 16) or TEK (n = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.
The Mediterranean Sea is an almost completely closed basin connecting several countries. Its configuration leads to its peculiarity and richness, but the intensive activities within the basin and along the coast aggravate the ecological conditions. The existing regulatory European Framework for environmental protection has already been in place through a series of legal instruments for almost 20 years. In this context, open science could play a fundamental role. The existing data must become findable, accessible, interoperable, and reusable (FAIR) to provide stakeholders and decision-makers with the instruments to understand how to improve the available information and support decisions based on the best set of existing information. Since 2009, the European Marine Observation and Data Network, EMODnet, has provided access to high-quality marine information supporting research and stakeholders’ mission and objectives. Data related to pollution are collated, validated, and published using standard protocols, formats, and vocabularies, thus becoming FAIR. For marine litter, a detailed and qualified data management system for macro- and microlitter in diverse compartments was structured. Some of these data and metadata were already used to calculate the first coastline litter baselines based on harmonized and FAIR datasets (2012–2016). The availability of these data related to the Mediterranean area is relevant, but additional work is required.
Introduction: In human obesity, chronic intermittent hypoxia (CIH) due to obstructive sleep apnoea induces NAFLD exacerbation. Whether this remains true in non-obese OSA is still debated. By contrast, CIH induced no adipose tissue (AT) histological modifications in morbidly obese. We aimed to evaluate the effect of a 14 days CIH on both liver, subcutaneous and epididymal AT in lean mice. Methods: 16 mice fed a chow-diet and were submitted to either normoxia or 8 hours of CIH.
Methods: After 14 days of exposure, expression of extra-cellular matrix, inflammatory and lipogenesis genes with PCR and immunohistological analysis were performed on liver and the two AT depots.
Results: In liver, CIH induced a significantly increased expression of gene involved in lipogenesis (ACC, SREBP1c, FAS), fibrosis (Coll1, Coll3, TGFβ), and inflammation (TNFα, IL1β) compared to mice on normoxia (at least two-fold ratio). However, this short CIH duration did not translate into histological lesions. Although mice submitted to CIH were significantly lighter than mice on normoxia, their epididymal AT was two-fold heavier in terms of percentage of total body weight. Furthermore, adipocyte size was increased in CIH along with increased leptin gene expression in epididymal AT (p=0.008). No difference was observed in inflammatory or extra-cellular matrix gene expression.
Conclusion: In lean mice, a short duration of CIH (14 days) already induces the features of NAFLD at the gene expression levels that do not yet translate into histological lesions. Furthermore, CIH also seems to impact on corpulence and adipose tissue characteristics.
