Search

Aims With the maturation of placenta, ventricular chamber maturation enhances cardiac contractile performance to adapt to the metabolic demand of growing embryo. The organization of cardiomyocytes is required for the morphological remodelling in ventricular chamber maturation. However, the mechanism governing the establishment of cardiac cytoarchitecture during ventricular chamber maturation is still poorly studied. Methods and results Here, we found that the expression of geranylgeranyl pyrophosphate synthase (Ggpps), which mediates protein geranylgeranylation, increased in the mouse heart after the onset of placental function. By using different Cre lines, we found that the cardiac inactivation of Ggpps by the Nkx2.5Cre/+ line disrupted protein geranylgeranylation as early as E9.5, which affected ventricular chamber maturation and resulted in mid-gestational embryonic lethality. In contrast, a-SMA-Cre line mediated the disruption of protein geranylgeranylation from E13.5 did not affect embryonic heart development. Further analysis of Nkx2.5Cre/+; Ggppsfl/fl mutants showed that the loss of Ggpps caused disorganized cardiac cytoarchitecture as early as E11.5 by disturbing cell-cell junctions. Ggpps inactivation decreased Rho GTPase geranylgeranylation and their activity, which might account for the disruption of cell-cell junctions. Moreover, elevating the protein geranylgeranylation by supplement of geranylgeranyl pyrophosphate (GGPP) could recover the Ggpps deficient induced defects of cytoarchitecture and cell-cell junctions in vitro and in vivo. Conclusion Our present study demonstrates that GGPPS-mediated protein geranylgeranylation plays an indispensable role in the ventricular chamber maturation and acts as a stage-specific signal to regulate the establishment of cardiac cytoarchitecture during mid-gestation. [ABSTRACT FROM AUTHOR]

Despite mounting pre-clinical and clinical evidence of the beneficial effects of cell-based therapy, optimal cell dosing and delivery approaches have not been identified. Cardiospheres are self-assembling three-dimensional (3 D) microtissues formed by cardiac stem cells and supporting cell types. The ability of cardiospheres to augment cardiac function has been demonstrated in animal models of ischemic cardiomyopathy. In this study, we studied the dose dependence of the benefits of human cardiospheres, delivered via intramyocardial injection, upon cardiac function and ventricular remodelling in SCID mice with acute myocardial infarction. Four doses of cardiospheres were used: 1 × 104, 5 × 104, 1 × 105 and 5 × 105 (expressed as number of plated cardiosphere-forming cells). Acute (24 hr) cell retention rates in all groups were similar. Functional assessment and quantitative heart morphometry indicated benefit from higher cell doses (≥5 × 104) in terms of ejection fraction, infarct size and capillary density. Histological analysis indicated that the dose-dependent benefit was primarily because of indirect effects of transplanted cells. The results provide scalable data on cardiosphere dosing for intramyocardial injection. [ABSTRACT FROM AUTHOR]

Abstract: Background: Radiotherapy of thoracic and chest wall tumors increases the long-term risk of cardiotoxicity, but the underlying mechanisms are unclear. Methods: Single doses of 2, 8, or 16Gy were delivered to the hearts of mice and damage was evaluated at 20, 40, and 60weeks, relative to age matched controls. Single photon emission computed tomography (SPECT/CT) and ultrasound were used to measure cardiac geometry and function, which was related to histo-morphology and microvascular damage. Results: Gated SPECT/CT and ultrasound demonstrated decreases in end diastolic and systolic volumes, while the ejection fraction was increased at 20 and 40weeks after 2, 8, and 16Gy. Cardiac blood volume was decreased at 20 and 60weeks after irradiation. Histological examination revealed inflammatory changes at 20 and 40weeks after 8 and 16Gy. Microvascular density in the left ventricle was decreased at 40 and 60weeks after 8 and 16Gy, with functional damage to remaining microvasculature manifest as decreased alkaline phosphatase (2, 8, and 16Gy), increased von Willebrand Factor and albumin leakage from vessels (8 and 16Gy), and amyloidosis (16Gy). 16Gy lead to sudden death between 30 and 40weeks in 38% of mice. Conclusions: Irradiation with 2 and 8Gy induced modest changes in murine cardiac function within 20weeks but this did not deteriorate further, despite progressive structural and microvascular damage. This indicates that heart function can compensate for significant structural damage, although higher doses, eventually lead to sudden death. [Copyright &y& Elsevier]