Association of ABCA1 R219K polymorphism and telomere length in a Chinese rural population: possible linking to systemic inflammation.

The ATP-binding cassette transporter A1 (ABCA1) gene polymorphisms have been shown to be associated with various human diseases and pathological conditions such as cardiovascular disease and Alzheimer's disease. However, these associations remain unclear and inconclusive. Interestingly, short telomere length was also observed in these diseases. In the present study, our aims were to investigate the interaction between two selected ABCA1 polymorphisms (-565C/T and R219K) and telomere length in a Chinese rural population including 1629 subjects and explore the underlying mechanisms. Genotyping was conducted using Taqman SNP Genotyping Assays. Mean relative leukocyte telomere length was measured using monochrome multiplex quantitative PCR method. We found that the telomere length of R219K RR genotype was significantly shorter than RK or KK genotypes (1.242 ± 0.198 vs 1.271 ± 0.207, P = 0.027 and 1.242 ± 0.198 vs 1.276 ± 0.209, P = 0.021, respectively). While the neutrophil to lymphocyte ratio (NLR) of R219K RR genotype was significantly higher than KK genotype (1.929 ± 0.826 vs 1.768 ± 0.893, P = 0.019). In the general linear models after adjustments for confounding factors, the KK and RK genotypes were both significantly associated with telomere length and NLR. A significant association was also observed for K allele carrier genotypes when compared with RR genotype for telomere length and NLR. In conclusion, the R219K polymorphism of ABCA1 was independently associated with telomere length. R219K K allele could be protective against shortening of telomeres and inflammation.

Recent advances in trophoblast cell-surface antigen 2 targeted therapy for solid tumors.

Trophoblast cell-surface antigen 2 (Trop 2) is a transmembrane glycoprotein that is highly expressed in various cancer types with relatively low or no baseline expression in most normal tissues. Its overexpression is associated with tumor growth and poor prognosis; Trop 2 is, therefore, an ideal therapeutic target for epithelial cancers. Several Trop 2 targeted therapeutics have recently been developed for the treatment of cancers, such as anti-Trop 2 antibodies and antibody-drug conjugates (ADCs), as well as Trop 2-specific cell therapy. In particular, the safety and clinical benefit of Trop 2-based ADCs have been demonstrated in clinical trials across multiple tumor types, including those with limited treatment options, such as triple-negative breast cancer, platinum-resistant urothelial cancer, and heavily pretreated non-small cell lung cancer. In this review, we elaborate on recent advances in Trop 2 targeted modalities and provide an overview of novel insights for future developments in this field.

ABCA1 Polymorphism Is Associated With the Warfarin-Induced Aortic Stiffness After Coronary Artery Bypass Surgery in the Chinese Population.

Warfarin is the most widely prescribed oral anticoagulant and is recommended for patients recovering from coronary artery bypass graft (CABG) with atrial fibrillation. Increasing evidence suggested that warfarin increased arterial stiffness in those patients. We aimed to examine the effect of warfarin therapy on aortic stiffness in patients who underwent CABG with or without postoperative warfarin treatment and explored the potential relationships of warfarin therapy with ABCA1 polymorphisms. This was a retrospect observational study of 24 patients who were continuously treated with warfarin were selected as the warfarin group and matched them by age (±3 years) and gender to 48 patients with nonuse of warfarin as the control group. The aortic stiffness, cholesterol efflux capacity, and plasma level of PIVKA-II were measured. Two ABCA1 polymorphisms were genotyped. Compared with baseline, treatment with warfarin for 1 year significantly increased the plasma level of PIVKA-II and aortic stiffness in pulse pressure and pulse wave velocity in patients after CABG. The increase of pulse wave velocity and plasma PIVKA-II level in the TT genotype was significantly greater than the CC genotype when comparing the -565C/T genotypes. The capacity of cholesterol efflux was significantly lower in the TT genotype at baseline and 1-year follow-up than the CC genotype. Postoperative treatment of warfarin for 1 year significantly increased aortic stiffness in patients who underwent CABG. ABCA1 -565C/T polymorphisms affected the cholesterol efflux capacity and were associated with the vitamin K status and the increased aortic stiffness after warfarin treatment in those patients.

Chronic dosing with metformin plus bosentan decreases in vitro pulmonary artery contraction from isolated arteries in adults with pulmonary hypertension.

Introduction: Pulmonary arterial hypertension (PAH) specific drug therapy using bosentan has significantly improved quality of life and survival, although PAH is still an incurable disease. Recent studies suggest metformin may have additional treatment benefits in PAH. We therefore investigated in vitro pulmonary artery reactivity after combination therapy of bosentan and metformin in PAH patients as compared with bosentan monotherapy in a prospective, randomized study. Methods: Adult patients with PAH associated with congenital heart defects (PAH-CHD) were randomised to receive bosentan (initially at 62.5 mg twice daily for 4 weeks and then 125 mg twice daily) for 3 months with or without the combination treatment of metformin (500 mg twice daily). Vessel reactivity of isolated pulmonary arteries was examined using a wire myograph. Results: Phenylephrine (PE)-induced contractions of arteries in patients received combination therapy were significantly attenuated at concentrations of 3 × 10-7 M, 10-6 M and 3 × 10-6 M, compared to those received bosentan monotherapy. After denudation, PE-induced contractions at concentrations of 3 × 10-6 M and 10-5 M were significantly decreased in the combination therapy group. AMP-activated protein kinase (AMPK) inhibitor compound C abrogated the inhibitory effects of metformin on PE-induced contractility. AMPK and eNOS phosphorylation in the pulmonary arteries of patients treated with combination therapy was increased compared to monotherapy (P < 0.05). Conclusion: Adding metformin to bosentan therapy in patients with PAH-CHD decreased in vitro pulmonary artery contraction induced by PE, which is possibly related to increased AMPK phosphorylation.

Increased maternal serum placental growth hormone variant in pregnancies complicated by otosclerosis.

OBJECTIVE: To investigate the potential role of maternal serum concentrations of placental growth hormone variant (GH-V), insulin-like growth factor (IGF) 1 and 2, and IGF-binding proteins (IGFBP) 1 and 3 in pregnancies complicated by otosclerosis. METHOD: Otosclerosis cases (n = 22) and age, ethnicity-matched controls (n = 22) were selected in a nested case-control study. Maternal serum hormone concentrations at 26 and 34 weeks of gestation were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Concentrations of all measured hormones except IGFBP-1 were increased as gestation progressed. Maternal serum GH-V concentrations at 26 and 34 weeks of gestation were significantly increased in the otosclerosis group, when compared to the control group (2.53 ± 0.17 ng/ml vs. 1.78 ± 0.19 ng/ml, P = 0.036; 4.34 ± 0.31 ng/ml vs. 3.12 ± 0.18 ng/ml, P < 0.001, respectively). Maternal serum IGF-1 concentrations at 34 weeks in otosclerotic patients were significantly higher than in the controls (589.1 ± 21.4 ng/ml vs. 499.7 ± 17.8 ng/ml, P < 0.001). The increase of IGF-1 was not observed at 26 weeks of gestation. Serum IGF-2, IGFBP-1 and IGFBP-3 at either 26 or 34 weeks were unaltered between the two groups. CONCLUSION: Maternal serum concentrations of GH-V and IGF-1 were altered in pregnancy complicated by otosclerosis, suggesting that the GH-IGF axis may contribute to the development of this condition during pregnancy.

Apolipoprotein A1 mimetic peptide ATI-5261 reverses arterial stiffness at late pregnancy and early postpartum in a COMT-/- mouse model of preeclampsia.

BACKGROUND: Preeclampsia (PE) is a serious maternal complication during pregnancy. Associated arterial stiffness in PE patients leads to increased risks of cardiovascular diseases later in life. Cholesterol efflux capacity, especially ATP binding cassette transporter A1 (ABCA1) dependent capacity, has been proposed to be a likely mediator of arterial stiffness. In the present study, we aimed to evaluate the effect of an apolipoprotein A1 mimetic peptide ATI-5261 on arterial stiffness in a mouse model of PE. METHODS: Pregnant COMT-/- mice were randomized to receive vehicle or ATI-5261 (30 mg/kg per day) via subcutaneous injection from gestational days (GD) 10.5 to GD 18.5 or to 10 days postpartum. Pregnant C57BL/6 J mice received vehicle during paralleled periods were served as normal controls. RESULTS: COMT-/- mice displayed maternal hypertension and proteinuria during pregnancy. Carotid-femoral pulse wave velocity (PWV) was increased at GD 18.5 and 10 days postpartum. ATI-5261 treatment in COMT-/- mice significantly reduced PWV and partially normalized impaired ex vivo vascular function at late pregnancy and early postpartum. ATI-5261 treatment also increased serum ABCA1 concentrations and cholesterol efflux capacity, as well as ABCA1 expressions in the placenta. Pup weights, crown to rump lengths and abdominal circumferences were reduced in COMT-/- mice. Treatment with ATI-5261 did not alter these fetal measurements but significantly reduced placental weights and increased fetal to placental ratios in COMT-/- mice. CONCLUSION: ATI-5261 reversed arterial stiffness at late pregnancy and early postpartum in a COMT-/- mouse model of PE and may be a potential therapy for arterial stiffness associated with PE.

Metformin added to bosentan therapy in patients with pulmonary arterial hypertension associated with congenital heart defects: a pilot study.

Pulmonary arterial hypertension (PAH) is a common complication of a congenital heart defect (CHD). Recent studies suggest metformin may be a potential drug to improve cardiac function in PAH. A pilot study was conducted to investigate the efficacy of short-term treatment with a combination regimen consisting of bosentan and metformin in PAH-CHD patients as compared with bosentan monotherapy in a prospective, randomised study. Patients with PAH-CHD were randomised to receive bosentan (initially at 62.5 mg twice daily for 4 weeks and then 125 mg twice daily) for 3 months with or without the combination treatment of metformin (500 mg twice daily). 93 patients were enrolled to bosentan monotherapy (n=48) or bosentan/metformin combination treatment (n=45). After 3 months, both treatments significantly improved World Health Organization functional class, 6-min walking distance (6MWD), N-terminal pro-brain natriuretic peptide and right heart haemodynamic parameters. The improvements in 6MWD and pulmonary vascular resistance index were significantly greater in patients treated with combination therapy than in those who received monotherapy (mean±sd 95±136 versus 48±119 m (p=0.017) and -1.8±1.2 versus -1.2±1.3 Wood units per m2 (p<0.001), respectively). Pulmonary endothelin (EDN)1 was significantly decreased after combination therapy (p=0.006). However, plasma EDN1 levels were not affected. Combination therapy with bosentan and metformin in PAH-CHD patients provides improvements in important outcomes such as exercise capacity and pulmonary haemodynamics, compared with bosentan alone.

Cholesterol Efflux: Does It Contribute to Aortic Stiffening?

Aortic stiffness during cardiac contraction is defined by the rigidity of the aorta and the elastic resistance to deformation. Recent studies suggest that aortic stiffness may be associated with changes in cholesterol efflux in endothelial cells. This alteration in cholesterol efflux may directly affect endothelial function, extracellular matrix composition, and vascular smooth muscle cell function and behavior. These pathological changes favor an aortic stiffness phenotype. Among all of the proteins participating in the cholesterol efflux process, ATP binding cassette transporter A1 (ABCA1) appears to be the main contributor to arterial stiffness changes in terms of structural and cellular function. ABCA1 is also associated with vascular inflammation mediators implicated in aortic stiffness. The goal of this mini review is to provide a conceptual hypothesis of the recent advancements in the understanding of ABCA1 in cholesterol efflux and its role and association in the development of aortic stiffness, with a particular emphasis on the potential mechanisms and pathways involved.

Human Placental Growth Hormone Variant in Pathological Pregnancies.

Growth hormone (GH), an endocrine hormone, primarily secreted from the anterior pituitary, stimulates growth, cell reproduction, and regeneration and is a major regulator of postnatal growth. Humans have two GH genes that encode two versions of GH proteins: a pituitary version (GH-N/GH1) and a placental GH-variant (GH-V/GH2), which are expressed in the syncytiotrophoblast and extravillous trophoblast cells of the placenta. During pregnancy, GH-V replaces GH-N in the maternal circulation at mid-late gestation as the major circulating form of GH. This remarkable change in spatial and temporal GH secretion patterns is proposed to play a role in mediating maternal adaptations to pregnancy. GH-V is associated with fetal growth, and its circulating concentrations have been investigated across a range of pregnancy complications. However, progress in this area has been hindered by a lack of readily accessible and reliable assays for measurement of GH-V. This review will discuss the potential roles of GH-V in normal and pathological pregnancies and will touch on the assays used to quantify this hormone.

Elastic aortic wrap reduced aortic stiffness by partially alleviating the impairment of cholesterol efflux capacity in pigs.

PURPOSE: Metabolic syndrome patients exhibit impaired cholesterol efflux capacity. Previous studies have shown a positive association between aortic stiffness and metabolic syndrome. However, it is unknown whether cholesterol efflux capacity participates in the process of aortic stiffness. This study sought to determine the effect of metabolic syndrome on aortic stiffening, and to investigate the effectiveness of aortic wraps on aortic compliance and the underlying mechanisms. METHODS: In a swine model of metabolic syndrome, we compared the cholesterol efflux capacity and aortic compliance responding to diet modifications and aortic wrap applications. RESULTS: Metabolic syndrome induced by high cholesterol diet significantly decreased cholesterol efflux capacity and aortic compliance. Elastic aortic wrap application increased aortic compliance and partially restored cholesterol efflux capacity via ATP binding cassette transporter A1 (ABCA1) pathway. CONCLUSIONS: Cholesterol efflux plays a role in aortic stiffening. Elastic aortic wrap application could be a potential treatment for aortic stiffness related to metabolic syndrome.

Maternal serum placental growth hormone, insulin-like growth factors and their binding proteins at 20 weeks' gestation in pregnancies complicated by gestational diabetes mellitus.

OBJECTIVE: To investigate whether maternal serum concentrations of placental growth hormone (GH-V), insulin-like growth factor (IGF) 1 and 2, and IGF binding proteins (IGFBP) 1 and 3 were altered in pregnancies complicated by gestational diabetes mellitus (GDM). METHOD: In a nested case-control study, GDM cases (n=28) and matched controls (n=28) were selected from the Screening for Pregnancy Endpoints (SCOPE) biobank in Auckland, New Zealand. Maternal serum hormone concentrations at 20 weeks of gestation were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: There was no significant difference in maternal serum GH-V concentration in the GDM group compared to the control group (1.64 ± 0.11 ng/ml vs. 1.38 ± 0.10 ng/ml, p=0.079). However, GDM cases who delivered large for gestational age (LGA) babies had significantly higher serum GH-V concentrations compared to non-diabetic control cases. Maternal IGF-1 concentrations in GDM pregnancies were significantly higher than in controls (275.7 ± 11.5 ng/ml vs. 218.5 ± 11.1 ng/ml, p <0.001). Maternal IGFBP-1 concentrations were significantly lower in GDM pregnancies than in controls (41.04 ± 3.42 ng/ml vs. 67.58 ± 6.17 ng/ml, p <0.001). There were no significant differences in serum IGF-2 and IGFBP-3 concentrations between groups. CONCLUSION: Concentrations of IGF-1 and IGFBP-1 in maternal serum were altered in GDM pregnancies compared to controls, suggesting that the IGF axis plays a role in the development of this condition. GH-V may be associated with macrosomia as increased maternal GH-V was observed in GDM cases who delivered LGA babies.

Maternal serum IGF-1, IGFBP-1 and 3, and placental growth hormone at 20weeks' gestation in pregnancies complicated by preeclampsia.

OBJECTIVE: To investigate whether maternal serum concentrations of placental growth hormone (GH-V), insulin-like growth factor (IGF) 1 and 2, and IGF binding proteins (IGFBP) 1 and 3 were altered in pregnancies complicated by later preeclampsia (PE). STUDY DESIGN: In a nested case-control study, PE cases (n=71) and matched controls (n=71) were selected from the Screening for Pregnancy Endpoints (SCOPE) biobank in Auckland, New Zealand. Maternal serum hormone concentrations at 20weeks of gestation were determined by ELISA. RESULTS: We found that maternal serum GH-V concentration at 20weeks of gestation was unaltered in the PE group, compared to the control group (median, 1.78ng/ml vs. 1.65ng/ml, p=0.884). Maternal IGF-1 and IGFBP-3 concentrations and the IGF-1/IGFBP-3 ratio in PE pregnancies were significantly higher than in controls (median, 253.1ng/ml vs. 204.3ng/ml, p<0.0001; 8535ng/ml vs. 7711ng/ml, p=0.0023; 0.032vs. 0.026, p<0.0001, respectively), whereas maternal IGFBP-1 concentration was significantly lower in PE pregnancies than in controls (median, 34.85ng/ml vs. 48.92ng/ml, p=0.0006). CONCLUSION: Our findings suggest a potential role of IGFs and IGFBPs in the prediction of pregnancies complicated by PE. However, the maternal serum concentration of GH-V at 20weeks' gestation is unlikely to be useful in the early prediction of PE.

Comparison of pulsatile vs. continuous administration of human placental growth hormone in female C57BL/6J mice.

Exogenous growth hormone has different actions depending on the method of administration. However, the effects of different modes of administration of the placental variant of growth hormone on growth, body composition and glucose metabolism have not been investigated. In this study, we examined the effect of pulsatile vs. continuous administration of recombinant variant of growth hormone in a normal mouse model. Female C57BL/6J mice were randomized to receive vehicle or variant of growth hormone (2 or 5 mg/kg per day) by daily subcutaneous injection (pulsatile) or osmotic pump for 6 days. Pulsatile treatment with 2 and 5 mg/kg per day significantly increased body weight. There was also an increase in liver, kidney and spleen weight via pulsatile treatment, whereas continuous treatment did not affect body weight or organ size. Pulsatile treatment with 5 mg/kg per day significantly increased fasting plasma insulin concentration, whereas with continuous treatment, fasting insulin concentration was not significantly different from the vehicle-treated control. However, a dose-dependent increase in fasting insulin concentration and decrease in insulin sensitivity, as assessed by HOMA, was observed with both modes of treatment. At 5 mg/kg per day, hepatic growth hormone receptor expression was increased compared to vehicle-treated animals, by both modes of administration. Pulsatile variant of growth hormone did not alter the plasma insulin-like growth factor-1 concentration, whereas a slight decrease was observed with continuous variant of growth hormone treatment. Neither pulsatile nor continuous treatment affected hepatic insulin-like growth factor-1 mRNA expression. Our findings suggest that pulsatile variant of growth hormone treatment was more effective in stimulating growth but caused marked hyperinsulinemia in mice.

Human placental growth hormone is increased in maternal serum at 20 weeks of gestation in pregnancies with large-for-gestational-age babies.

To investigate the relationship between maternal serum concentrations of placental growth hormone (GH-V), insulin-like growth factor (IGF)-1 and 2, IGF binding proteins (IGFBP)-1 and 3 and birth weight in appropriate-for-gestational-age (AGA), large-for-gestational-age (LGA) and small-for-gestational-age (SGA) cases in a nested case-control study. Maternal serum samples were selected from the Screening for Pregnancy Endpoints (SCOPE) biobank in Auckland, New Zealand. Serum hormone concentrations were determined by ELISA. We found that maternal serum GH-V concentrations at 20 weeks of gestation in LGA pregnancies were significantly higher than in AGA and SGA pregnancies. Maternal GH-V concentrations were positively correlated to birth weights and customized birth weight centiles, while IGFBP-1 concentrations were inversely related to birth weights and customized birth weight centiles. Our findings suggest that maternal serum GH-V and IGFBP-1 concentrations at 20 weeks' gestation are associated with fetal growth.

The Placental Variant of Human Growth Hormone Reduces Maternal Insulin Sensitivity in a Dose-Dependent Manner in C57BL/6J Mice.

The human placental GH variant (GH-V) is secreted continuously from the syncytiotrophoblast layer of the placenta during pregnancy and is thought to play a key role in the maternal adaptation to pregnancy. Maternal GH-V concentrations are closely related to fetal growth in humans. GH-V has also been proposed as a potential candidate to mediate insulin resistance observed later in pregnancy. To determine the effect of maternal GH-V administration on maternal and fetal growth and metabolic outcomes during pregnancy, we examined the dose-response relationship for GH-V administration in a mouse model of normal pregnancy. Pregnant C57BL/6J mice were randomized to receive vehicle or GH-V (0.25, 1, 2, or 5 mg/kg · d) by osmotic pump from gestational days 12.5 to 18.5. Fetal linear growth was slightly reduced in the 5 mg/kg dose compared with vehicle and the 0.25 mg/kg groups, respectively, whereas placental weight was not affected. GH-V treatment did not affect maternal body weights or food intake. However, treatment with 5 mg/kg · d significantly increased maternal fasting plasma insulin concentrations with impaired insulin sensitivity observed at day 18.5 as assessed by homeostasis model assessment. At 5 mg/kg · d, there was also an increase in maternal hepatic GH receptor/binding protein (Ghr/Ghbp) and IGF binding protein 3 (Igfbp3) mRNA levels, but GH-V did not alter maternal plasma IGF-1 concentrations or hepatic Igf-1 mRNA expression. Our findings suggest that at higher doses, GH-V treatment can cause hyperinsulinemia and is a likely mediator of the insulin resistance associated with late pregnancy.