J. Cardiovasc. Dev. Dis.2015, 2(1), 17-30; doi:10.3390/jcdd2010017 - published 9 March 2015 Show/Hide Abstract
Abstract: Thoracic aortic aneurysms (TAA) are a significant cause of morbidity and mortality in humans. While the exact etiology is unknown, genetic factors play an important role. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV) and aortopathy in humans. The aim of this study was to determine if haploinsufficiency of Notch1 contributes to aortopathy using Notch1+/−; Nos3−/−mice. Echocardiographic analysis of Notch1+/−; Nos3−/−mice reveals effacement of the sinotubular junction and a trend toward dilation of the aortic sinus. Furthermore, examination of the proximal aorta of Notch1+/−; Nos3−/− mice reveals elastic fiber degradation, a trend toward increased matrix metalloproteinase 2 expression, and increased smooth muscle cell apoptosis, features characteristic of aneurysmal disease. Although at a lower penetrance, we also found features consistent with aortopathic changes in Notch1 heterozygote mice and in Nos3-null mice. Our findings implicate a novel role for Notch1 in aortopathy of the proximal aorta.
J. Cardiovasc. Dev. Dis.2015, 2(1), 2-16; doi:10.3390/jcdd2010002 - published 16 February 2015 Show/Hide Abstract
Abstract: Many of the major discoveries in the fields of genetics and developmental biology have been made using the fruit fly, Drosophila melanogaster. With regard to heart development, the conserved network of core cardiac transcription factors that underlies cardiogenesis has been studied in great detail in the fly, and the importance of several signaling pathways that regulate heart morphogenesis, such as Slit/Robo, was first shown in the fly model. Recent technological advances have led to a large increase in the genomic data available from patients with congenital heart disease (CHD). This has highlighted a number of candidate genes and gene networks that are potentially involved in CHD. To validate genes and genetic interactions among candidate CHD-causing alleles and to better understand heart formation in general are major tasks. The specific limitations of the various cardiac model systems currently employed (mammalian and fish models) provide a niche for the fly model, despite its evolutionary distance to vertebrates and humans. Here, we review recent advances made using the Drosophila embryo that identify factors relevant for heart formation. These underline how this model organism still is invaluable for a better understanding of CHD.
J. Cardiovasc. Dev. Dis.2014, 1(3), 237-256; doi:10.3390/jcdd1030237 - published 1 December 2014 Show/Hide Abstract
Abstract: Aortic valve disease is a burgeoning public health problem associated with significant mortality. Loss of function mutations in NOTCH1 cause bicuspid aortic valve (BAV) and calcific aortic valve disease. Because calcific nodules manifest on the fibrosa side of the cusp in low fluidic oscillatory shear stress (OSS), elucidating pathogenesis requires approaches that consider both molecular and mechanical factors. Therefore, we examined the relationship between NOTCH loss of function (LOF) and biomechanical indices in healthy and diseased human aortic valve interstitial cells (AVICs). An orbital shaker system was used to apply cyclic OSS, which mimics the cardiac cycle and hemodynamics experienced by AVICs in vivo. NOTCH LOF blocked OSS-induced cell alignment in human umbilical vein endothelial cells (HUVECs), whereas AVICs did not align when subjected to OSS under any conditions. In healthy AVICs, OSS resulted in decreased elastin (ELN) and α-SMA (ACTA2). NOTCH LOF was associated with similar changes, but in diseased AVICs, NOTCH LOF combined with OSS was associated with increased α-SMA expression. Interestingly, AVICs showed relatively higher expression of NOTCH2 compared to NOTCH1. Biomechanical interactions between endothelial and interstitial cells involve complex NOTCH signaling that contributes to matrix homeostasis in health and disorganization in disease.
J. Cardiovasc. Dev. Dis.2014, 1(3), 214-236; doi:10.3390/jcdd1030214 - published 20 November 2014 Show/Hide Abstract
Abstract: The initial heart is composed of a myocardial tube lined by endocardial cells. The TGFβ superfamily is known to play an important role, as BMPs from the myocardium signal to the overlying endocardium to create an environment for EMT. Subsequently, BMP and TGFβ signaling pathways synergize to form primitive valves and regulate myocardial growth. In this study, we investigated the requirement of BMP activity by transgenic over-expression of extracellular BMP antagonist Noggin. Using Nfatc1Cre to drive lineage-restricted Noggin within the endocardium, we show that ectopic Noggin arrests cardiac development in E10.5-11 embryos, resulting in small hearts which beat poorly and die by E12.5. This is coupled with hypoplastic endocardial cushions, reduced trabeculation and fewer mature contractile fibrils in mutant hearts. Moreover, Nfatc1Cre-mediated diphtheria toxin fragment-A expression in the endocardium resulted in genetic ablation and a more severe phenotype with lethality at E11 and abnormal linear hearts. Molecular analysis demonstrated that endocardial Noggin resulted in a specific alteration of TGFβ/BMP-mediated signal transduction, in that, both Endoglin and ALK1 were downregulated in mutant endocardium. Combined, these results demonstrate the cell-autonomous requirement of the endocardial lineage and function of unaltered BMP levels in facilitating endothelium-cardiomyocyte cross-talk and promoting endocardial cushion formation.
J. Cardiovasc. Dev. Dis.2014, 1(3), 201-213; doi:10.3390/jcdd1030201 - published 10 October 2014 Show/Hide Abstract
Abstract: Despite gaining focus, cardiovascular disease (CVD) remains the leading cause of death worldwide. Health promotion agencies have traditionally recommended diets that are low in fat in order to reduce CVD risk however, much debate remains about which dietary approaches are the most efficient for effective disease prevention. Common markers of CVD include elevated plasma triglycerides (TG) and low-density lipoprotein (LDL) cholesterol levels, as well as reduced high-density lipoprotein (HDL) cholesterol levels. While weight loss alone can significantly reduce markers of CVD, manipulating dietary macronutrient content contributes to the beneficial effects of weight loss and furthers the improvement of lipid profiles even without the alteration of total caloric intake. Considering the recent attention to diets that are low in carbohydrates rather than fat, it remains to be elucidated the beneficial effects of each diet type when establishing new recommendations for CVD prevention. This review aims to examine the effects of different macronutrient compositions on lipid markers, thus providing insight into the potential roles of various diet types in the targeted prevention against CVD.