Hypoglycemia induced changes in cell death and cell proliferation in the organogenesis stage embryonic mouse heart

Ghatnekar, Gautam S.; Barnes, Jill A.; Dow, Janet L.; Smoak, Ida W.

doi:10.1002/bdra.20000

Cited by 6 publications

(1 citation statement)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After dewaxing, Hoechst-stained nuclei were imaged using a DAPI/Hoechst/ AMA filter cube (excitation, 360 nm; emission, 469 nm; Chroma) and LysoTracker was detected with a G2A cube. As reported in other studies (Ghatnekar et al, 2004;Zucker et al, 1999), pilot experiments in B6CBA/J F2 conceptuses confirmed the specificity of LysoTracker Red uptake. Briefly, apoptotic cells were detected in B6CBA/J F2 conceptuses primarily within the neurectoderm (LB to LHF stages), with a few positive cells in the allantoic core (data not shown).…”

Section: Lysotracker Red Stainingsupporting

confidence: 87%

Brachyury is required for elongation and vasculogenesis in the murine allantois

2006

View full text Add to dashboard Cite

Mouse conceptuses homozygous for mutations in brachyury (T)exhibit a short, misshapen allantois that fails to fuse with the chorion. Ultimately, mutant embryos die during mid-gestation. In the 60 years since this discovery, the role of T in allantoic development has remained obscure. T protein was recently identified in several new sites during mouse gastrulation, including the core of the allantois, where its function is not known. Here, using molecular, genetic and classical techniques of embryology,we have investigated the role of T in allantoic development. Conceptuses homozygous for the TCurtailed(TC) mutation (TC/TC)exhibited allantoic dysmorphogenesis shortly after the allantoic bud formed. Diminution in allantoic cell number and proliferation was followed by cell death within the core. Fetal liver kinase (Flk1)-positive angioblasts were significantly decreased in TC/TC allantoises and did not coalesce into endothelial tubules, possibly as a result of the absence of platelet endothelial cell adhesion molecule 1 (Pecam1), whose spatiotemporal relationship to Flk1 suggested a role in patterning the umbilical vasculature. Remarkably, microsurgical perturbation of the wild-type allantoic core phenocopied the TC/TCvascularization defect, providing further support that an intact core is essential for vascularization. Last, abnormalities were observed in the TC/TC heart and yolk sac, recently reported sites of T localization. Our findings reveal that T is required to maintain the allantoic core, which is essential for allantoic elongation and vascular patterning. In addition, morphological defects in other extraembryonic and embryonic vascular organs suggest a global role for T in vascularization of the conceptus.

show abstract

Section: Lysotracker Red Stainingsupporting

confidence: 87%

Brachyury is required for elongation and vasculogenesis in the murine allantois

2006

View full text Add to dashboard Cite

show abstract

The proarrhythmic effect of hypoglycemia: evidence for increased risk from ischemia and bradycardia

Nordin

2013

Acta Diabetol

View full text Add to dashboard Cite

Hypoglycemia increases the risk for both overall and sudden death. At a cellular level, hypoglycemia causes alterations in the physiology of myocardial tissue that are identical to proarrhythmic medications. Reduced serum glucose blocks the repolarizing K(+) channel HERG, which leads to action potential and QT prolongation and is uniformly associated with risk for torsades de pointes ventricular tachycardia. The sympathetic response induced by hypoglycemia also increases the risk of arrhythmias from Ca(2+) overload, which occur with sympathomimetic medications and excessive beta adrenergic stimulation. Thus, hypoglycemia can be considered a proarrhythmic event. This review focuses on emerging evidence for two other important changes induced by hypoglycemia that promote arrhythmias: ischemia and bradycardia. Studies of patients with "insulin shock" therapy from the early twentieth century and other more recent data strongly suggest that hypoglycemia can cause ischemia of myocardial tissue, both in association with coronary artery obstructions and by cellular mechanisms. Ischemia induces multiple proarrhythmic responses. Since ischemia itself reduces the possibility of using energy substrates other than glucose, hypoglycemia may generate positive feedback for electrophyisologic destabilization. Recent studies also show that hypoglycemia can cause bradycardia and heart block. Bradycardia is known to cause action potential prolongation and potentiate the development of torsades de pointes, particularly with low-serum K(+) which can be induced by hypoglycemic episodes. Thus, hypoglycemia-induced bradycardia may also create a dynamic, positive feedback for the development of arrhythmias and sudden death. These studies further support the hypothesis that hypoglycemia is a proarrhythmic event.

show abstract

Nonclinical Safety Evaluation of Muraglitazar, a Novel PPARα/γ Agonist

Waites

Dominick

Sanderson

et al. 2007

Toxicological Sciences

View full text Add to dashboard Cite

The toxicity of muraglitazar, an oxybenzylglycine, nonthiazolidinedione peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, was evaluated in a comprehensive nonclinical toxicology program that included single-dose oral toxicity studies in mice, rats, and monkeys; repeat-dose toxicity studies in rats, dogs, and monkeys; a battery of in vitro and in vivo genetic toxicity studies; carcinogenicity studies in mice and rats; reproductive and developmental toxicity studies in rats and rabbits; and studies to investigate species-specific findings. Pharmacologically mediated changes, similar to those observed with other PPARgamma agonists, were observed following chronic administration and included subcutaneous edema, hematologic/hematopoietic and serum chemistry alterations, and morphologic findings in the heart and adipose tissue in rats and monkeys. In dogs, a species highly sensitive to PPARgamma agonists, muraglitazar caused pronounced species-specific clinical toxicity and degenerative changes in the brain, spinal cord, and testes at high doses and exposures. Muraglitazar was nongenotoxic in the standard battery of genotoxicity studies. Gallbladder adenomas in male mice and adipocyte neoplasms in male and female rats were seen at suprapharmacologic exposures, whereas urinary bladder tumors occurred in male rats at lower exposures. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Muraglitazar had no effects on reproductive function in male and female rats at high systemic exposures, was not teratogenic in rats or rabbits, and demonstrated no selective developmental toxicity. Overall, there were no nonclinical findings that precluded the safe administration of muraglitazar to humans.

show abstract

Hypoglycemia induced changes in cell death and cell proliferation in the organogenesis stage embryonic mouse heart

Abstract: Hypoglycemia reduces embryonic viability, induces significant cell death, and reduces cell proliferation in the E9.5 mouse heart, and these processes may involve active caspase-3 and p53.

Cited by 6 publications

References 58 publications

Brachyury is required for elongation and vasculogenesis in the murine allantois

Brachyury is required for elongation and vasculogenesis in the murine allantois

The proarrhythmic effect of hypoglycemia: evidence for increased risk from ischemia and bradycardia

Nonclinical Safety Evaluation of Muraglitazar, a Novel PPARα/γ Agonist

Contact Info

Product

Resources

About