Primary cilia are crucial for normal cardiac organogenesis via the formation of cyto-architectural, anatomical, and physiological boundaries in the developing heart and outflow tract. These tiny, plasma membrane-bound organelles function in a sensory-integrative capacity, interpreting both the intra- and extra-cellular environments and directing changes in gene expression responses to promote, prevent, and modify cellular proliferation and differentiation. One distinct feature of this organelle is its involvement in the propagation of a variety of signaling cascades, most notably, the Hedgehog cascade. Three ligands, Sonic, Indian, and Desert hedgehog, function as growth factors that are most commonly dependent on the presence of intact primary cilia, where the Hedgehog receptors Patched-1 and Smoothened localize directly within or at the base of the ciliary axoneme. Hedgehog signaling functions to mediate many cell behaviors that are critical for normal embryonic tissue/organ development. However, inappropriate activation and/or upregulation of Hedgehog signaling in postnatal and adult tissue is known to initiate oncogenesis, as well as the pathogenesis of other diseases. The focus of this review is to provide an overview describing the role of Hedgehog signaling and its dependence upon the primary cilium in the cell types that are most essential for mammalian heart development. We outline the breadth of developmental defects and the consequential pathologies resulting from inappropriate changes to Hedgehog signaling, as it pertains to congenital heart disease and general cardiac pathophysiology.
IntroductionCardiovascular disease (CVD) mortality is higher among breast cancer survivors (BCS) who receive chemotherapy compared with those not receiving chemotherapy. Anthracycline chemotherapy is of particular concern due to anthracycline-related impairment of vascular endothelial cells and dysregulation of the extracellular matrix. One strategy proven to offset these impairments is a form of exercise known as high-intensity interval training (HIIT). HIIT improves endothelial function in non-cancer populations by decreasing oxidative stress, the main contributor to anthracycline-induced vascular dysfunction. The purpose of this pilot study is to assess the feasibility of an 8-week HIIT, as well as the HIIT effects on endothelial function and extracellular matrix remodelling, in BCS undergoing anthracycline chemotherapy.Methods and analysisThirty BCS are randomised to either HIIT, an 8-week HIIT intervention occurring three times per week (seven alternating bouts of 90% of peak power output followed by 10% peak power output), or delayed group (DEL). Feasibility of HIIT is assessed by (1) the percentage of completed exercise sessions and (2) the number of minutes of exercise completed over the course of the study. Vascular function is assessed using brachial artery flow-mediated dilation and carotid intima media thickness. Extracellular matrix remodelling is assessed by the level of matrix metalloproteinases in the plasma. A repeated-measures analysis of covariance model will be performed with group (HIIT and DEL group) and time (pre/post assessment) as independent factors. We hypothesise that HIIT will be feasible in BCS undergoing anthracycline chemotherapy, and that HIIT will improve endothelial function and extracellular matrix remodelling, compared with the DEL group. Success of this study will provide evidence of feasibility and efficacy to support a larger definitive trial which will impact cancer survivorship by decreasing anthracycline-induced vascular dysfunction, thereby benefiting cardiovascular markers that are related to CVD risk.Ethics and disseminationThis trial was approved by the University of Southern California Institutional Review Board (HS-15–00227).Trial registration numberNCT02454777.
Congenital heart defects (CHD) affect approximately 8 out of every 1,000 newborns, resulting in the birth of 35,000 babies with CHD annually in the United States. Primary cilia are small, finger‐like structures that extend from almost all eukaryotic cells and have been found to play a pivotal role in both development and maturation of embryonic and perinatal heart. Our laboratory presents a novel cardiac phenotype resulting from the elimination of primary cilia from cardiac neural crest cells (cNCC) of the embryonic mouse heart. This phenotype combines a high incidence of outflow tract defects, including double‐outlet right ventricle, with severe damage to the membranous interventricular septum, non‐compaction of the developing ventricular myocardium, and perinatal lethality. The purpose of this ongoing project is to develop a reliable method for obtaining electrocardiograms (ECG) in perinatal mice, to perform a comprehensive and diagnostic analysis of the combined anatomical and physiological data and to better understand the perinatal lethality resulting from primary cilia elimination. A Cre recombinase‐expressing mouse (Wnt1:Cre) was crossed with the Ift88flox/flox mouse, resulting in elimination of primary cilia from cNCC during mid embryonic heart development. Extensive histological and imaging analyses were previously performed to characterize and reconstruct the anatomical abnormalities. Perinatal electrocardiography (ECG) was then performed on 34 pups within the first day of life (P1), where mice remained conscious in the prone position. Modified gel‐coated ECG electrodes were placed in the right axilla of the left lower quadrant of the abdomen, allowing for a two‐lead electrophysiological evaluation. ECGs were collected for a total of 5 minutes, after which, pups were euthanized for further histological evaluation. ECG analysis included heart rate (HR; minimum, maximum and mean), QRS duration, P wave presence, PR interval, and overall ECG interpretation. Mutant mice (n=26) demonstrated a significantly lower HR when compared to littermate wildtype (WT) (n=8) mice (233±24 beats per minute (bpm) vs 30±2 bpm, p<0.0001). QRS duration was significantly lengthened in the mutant mice compared with WT (0.020±0.001 milliseconds (ms) vs 0.014±0.001 ms, p=0.018). P wave activity was absent in 54% of mutant mice when compared to 100% appearance in WT mice. Combined incidence of bradycardia, HR irregularity and the absence of P wave activity seen in the mutant mice suggests that the QRS complexes demonstrated were not sinus in nature, rather of a junctional or ventricular origin. Whether this is due to a defect in SA node development, communication between the atria and ventricles, or hypoxia is currently under investigation. Increased QRS duration seen in mutant mice is suggestive of additional depolarization abnormalities. Collectively, these results characterize a relationship between the anatomical phenotype resulting from primary cilia elimination and abnormal embryological development of cardiac electrical conduction pathways.Support or Funding InformationGenerous support for this project was made possible by the Saving tiny Hearts Foundation and the Peter Morgane Fellowship Program at the University of New England.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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