👤 Dörte Becher

Polycystic ovary syndrome (PCOS) is associated with increased cardiometabolic risk in young women of reproductive age. There are limited studies on atherogenic dyslipidemia, inclusive of triglycerides (TG), Apolipoprotein (apo) B-lipoproteins and remnant-cholesterol (C), atherosclerotic cardiovascular disease (ACVD), cardiac function and remodeling in young women with and without PCOS. The aim of this pilot study was to investigate the relationship of atherogenic dyslipidemia and other cardiometabolic risk factors with ACVD, cardiac function-remodeling in high-risk young overweight-obese PCOS women compared to non-PCOS and healthy-weight controls. Women with and without PCOS (non-PCOS control) aged 18 - 45 years who were overweight and obese (>25kg/m PCOS (n=48) and non-PCOS control overweight-obese age-BMI matched groups (n=19) were shown to have significantly higher fasting and non-fasting lipids including TG, remnant-C, total ApoB and ApoB48, compared to healthy-weight non-PCOS controls (n=10). PCOS and non-PCOS control overweight-obese groups had significantly higher SBP, DBP, cIMT and evidence of cardiac dysfunction and remodeling, with reduced Mitral E/A ratio, intraventricular (IV) relaxation time and increased Left ventricle (LV) end diastolic and systolic diameter, LV posterior wall thickness and IV septal thickness, compared to healthy-weight non-PCOS controls. Individuals with PCOS had significantly higher fasting plasma TG and remnant-C compared to the non-PCOS overweight-obese control group. The PCOS group tended to have 25% higher carotid plaque height, although this was not significant, compared to the non-PCOS overweight-obese control group. DBP, HOMA-IR and ApoB predicted 40% of the variability in cIMT and ApoB was shown to predict 14% of the variability in carotid plaque height, independent of age and BMI. A 1mg/ml increase in ApoB was associated with a 0.041mm increase in cIMT and a 0.75mm increase in carotid plaque height in all young women. Our pilot results supports the potential of apoB-dyslipidemia, cIMT, carotid plaque height and left ventricular diastolic dysfunction and remodeling to be used in screening for CVD risk in high-risk populations such as overweight-obese women with and without PCOS. ApoB may be useful to predict atherosclerotic vascular burden and progression of cIMT and carotid plaque, and could be used to develop a female specific algorithm for ACVD risk in high-risk young women with and without PCOS. Show less

The opportunistic pathogen Legionella pneumophila employs the Icm/Dot type IV secretion system and ∼300 different effector proteins to replicate in macrophages and amoebae in a distinct 'Legionella-containing vacuole' (LCV). LCVs from infected RAW 264.7 macrophages were enriched by immuno-affinity separation and density gradient centrifugation, using an antibody against the L. pneumophila effector SidC, which specifically binds to the phosphoinositide PtdIns(4)P on the pathogen vacuole membrane. The proteome of purified LCVs was determined by mass spectro-metry (data are available via ProteomeXchange with identifier PXD000647). The proteomics analysis revealed more than 1150 host proteins, including 13 small GTPases of the Rab family. Using fluorescence microscopy, 6 novel Rab proteins were confirmed to localize on pathogen vacuoles harbouring wild-type but not ΔicmT mutant L. pneumophila. Individual depletion of 20 GTPases by RNA interference indicated that endocytic GTPases (Rab5a, Rab14 and Rab21) restrict intracellular growth of L. pneumophila, whereas secretory GTPases (Rab8a, Rab10 and Rab32) implicated in Golgi-endosome trafficking promote bacterial replication. Upon silencing of Rab21 or Rab32, fewer LCVs stained positive for Rab4 or Rab9, implicated in secretory or retrograde trafficking respectively. Moreover, depletion of Rab8a, Rab14 or Rab21 significantly decreased the number of SidC-positive LCVs, suggesting that PtdIns(4)P is reduced under these conditions. L. pneumophila proteins identified in purified LCVs included proteins putatively implicated in phosphorus metabolism and as many as 60 Icm/Dot-translocated effectors, which are likely required early during infection. Taken together, the phagocyte and Legionella proteomes of purified LCVs lay the foundation for further hypothesis-driven investigations of the complex process of pathogen vacuole formation. Show less