Fibroblast activation protein: Pivoting cancer/chemotherapeutic insight towards heart failure.

An important mechanism for cancer progression is degradation of the extracellular matrix (ECM) which is accompanied by the emergence and proliferation of an activated fibroblast, termed the cancer associated fibroblast (CAF). More specifically, an enzyme pathway identified to be amplified with local cancer progression and proliferation of the CAF, is fibroblast activation protein (FAP). The development and progression of heart failure (HF) irrespective of the etiology is associated with left ventricular (LV) remodeling and changes in ECM structure and function. As with cancer, HF progression is associated with a change in LV myocardial fibroblast growth and function, and expresses a protein signature not dissimilar to the CAF. The overall goal of this review is to put forward the postulate that scientific discoveries regarding FAP in cancer as well as the development of specific chemotherapeutics could be pivoted to target the emergence of FAP in the activated fibroblast subtype and thus hold translationally relevant diagnostic and therapeutic targets in HF.

Maternal vitamin D sufficiency and reduced placental gene expression in angiogenic biomarkers related to comorbidities of pregnancy.

INTRODUCTION: Maternal circulating 25-hydroxyvitamin D [25(OH)D] has been shown to optimize production of 1,25-dihydroxyvitamin D [1,25(OH)2D] during pregnancy at approximately 100nmoles/L, which has pronounced effects on fetal health outcomes. Additionally, associations are noted between low maternal 25(OH)D concentrations and vascular pregnancy complications, such as preeclampsia. To further elucidate the effects of vitamin D activity in pregnancy, we investigated the role of maternal 25(OH)D, the nutritional indicator of vitamin D status, in relation to placental maintenance and, specifically, expression of placental gene targets related to angiogenesis and vitamin D metabolism. METHODS: A focused analysis of placental mRNA expression related to angiogenesis, pregnancy maintenance, and vitamin D metabolism was conducted in placentas from 43 subjects enrolled in a randomized controlled trial supplementing 400IU or 4400IU of vitamin D3 per day during pregnancy. Placental mRNA was isolated from biopsies within one hour of delivery, followed by quantitative PCR. We classified pregnant women with circulating concentrations of <100nmoles/L as deficient and those with ≥100nmoles/L as sufficient. The value of each gene's change in the PCR cycle threshold (ΔCT), which is a relative measure of target concentration, was compared with maternal 25(OH)D concentrations <100nmoles/L and ≥100nmoles/L based on a two-sample Wilcoxon test. RESULTS: Soluble FMS-like tyrosine kinase 1 (sFlt-1) and vascular endothelial growth factor (VEGF) gene expression was significantly downregulated in the maternal subgroup with circulating 25(OH)D ≥100ng/mL compared to the subgroup <100ng/mL. DISCUSSION: Here, we report a significant association between maternal vitamin D status and the expression of sFlt-1 and VEGF at the mRNA level. Achieving maternal circulating 25(OH)D ≥100nmoles/L suggests the impact of maternal vitamin D3 supplementation on gene transcription in the placenta, thereby potentially decreasing antiangiogenic factors that may contribute to vascular pregnancy complications.