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Induction of the cell cycle is emerging as an intervention to treat heart failure. Here, we tested the hypothesis that enhanced cardiomyocyte renewal in transgenic mice expressing cyclin D2 would be beneficial during hemodynamic overload. We induced pressure overload by transthoracic aortic constriction (TAC) or volume overload by aortocaval shunt in cyclin D2expressing and WT mice. Although cyclin D2 expression dramatically improved survival following TAC, it did not confer a survival advantage to mice following aortocaval shunt. Cardiac function decreased following TAC in WT mice, but was preserved in cyclin D2-expressing mice. On the other hand, cardiac structure and function were compromised in response to aortocaval shunt in both WT and cyclin D2-expressing mice. The preserved function and improved survival in cyclin D2expressing mice after TAC was associated with an approximately 50% increase in cardiomyocyte number and exaggerated cardiac hypertrophy, as indicated by increased septum thickness. Aortocaval shunt did not further impact cardiomyocyte number in mice expressing cyclin D2. Following TAC, cyclin D2 expression attenuated cardiomyocyte hypertrophy, reduced cardiomyocyte apoptosis, fibrosis, calcium/calmodulin-dependent protein kinase IIS phosphorylation, brain natriuretic peptide expression, and sustained capillarization. Thus, we show that cyclin D2-induced cardiomyocyte renewal reduced myocardial remodeling and dysfunction after pressure overload but not after volume overload., Introduction In structural heart diseases, increased ventricular load is a key trigger mechanism for altered gene expression and cardiac remodeling (1). Increased ventricular load translates into increased wall stress for [...]

Uniparental parthenotes are considered an unwanted byproduct of in vitro fertilization. In utero parthenote development is severely compromised by defective organogenesis and in particular by defective cardiogenesis. Although developmentally compromised, [...]

The functional heart is comprised of distinct mesoderm-derived lineages including cardiomyocytes, endothelial cells and vascular smooth muscle cells. Studies in the mouse embryo and the mouse embryonic stem cell differentiation [...]

A transgenic mouse model was developed to examine the role of nerve growth factor (NGF) during sensory neural development. In the model, NGF expression was increased by placing a NGF minigene under the transcriptional control of the cardiac-specific alpha-myosin heavy chain promoter. Immunohistochemical analysis revealed subpopulation of ectopic cells derived from the neural crest and an increase in myocardial mass. This suggests that increased NGF is produced by hyperinnervation of the heart and expansion of neural crest-cell types.

A reciprocal study in which endogenous skeletal troponin (sTnC) was removed from permeabilized rapid psoas skeletal muscle fibers and substituted with distilled exogenous cardiac troponin C (cTnC), is conducted. TnC has a significant function in examining cardiac muscle sensitivity to acidosis and its therapeutic mediations.

Aims To examine the role of the basic Helix-loop-Helix (bHLH) transcription factor HAND1 in embryonic and adult myocardium. Methods and results Hand1 is expressed within the cardiomyocytes of the left ventricle (LV) and myocardial cuff between embryonic days (E) 9.5–13.5. Hand gene dosage plays an important role in ventricular morphology and the contribution of Hand1 to congenital heart defects requires further interrogation. Conditional ablation of Hand1 was carried out using either Nkx2.5 knockin Cre (Nkx2.5Cre) or α-myosin heavy chain Cre (α Mhc-Cre) driver. Interrogation of transcriptome data via ingenuity pathway analysis reveals several gene regulatory pathways disrupted including translation and cardiac hypertrophy-related pathways. Embryo and adult hearts were subjected to histological, functional, and molecular analyses. Myocardial deletion of Hand1 results in morphological defects that include cardiac conduction system defects, survivable interventricular septal defects, and abnormal LV papillary muscles (PMs). Resulting Hand1 conditional mutants are born at Mendelian frequencies; but the morphological alterations acquired during cardiac development result in, the mice developing diastolic heart failure. Conclusion Collectively, these data reveal that HAND1 contributes to the morphogenic patterning and maturation of cardiomyocytes during embryogenesis and although survivable, indicates a role for Hand1 within the developing conduction system and PM development. [ABSTRACT FROM AUTHOR]

Aims Doxorubicin (DOX) is a widely used and effective anti-cancer therapeutic. DOX treatment is associated with both acute and late onset cardiotoxicity, limiting its overall efficacy. Here, the impact of cardiomyocyte cell cycle activation was examined in a juvenile model featuring aspects of acute and late onset DOX cardiotoxicity. Methods and results Two-week old MHC-cycD2 transgenic mice (which express cyclin D2 in postnatal cardiomyocytes and exhibit sustained cardiomyocyte cell cycle activity; D2 mice) and their wild type (WT) littermates received weekly DOX injections for 5 weeks (25 mg/kg cumulative dose). One week after the last DOX treatment (acute stage), cardiac function was suppressed in both groups. Acute DOX cardiotoxicity in D2 and WT mice was associated with similar increases in the levels of cardiomyocyte apoptosis and Ku70/Ku80 expression (markers of DNA damage and oxidative stress), as well as similar reductions in hypertrophic cardiomyocyte growth. Cardiac dysfunction persisted in WT mice for 13 weeks following the last DOX treatment (late stage) and was accompanied by increased levels of cardiomyocyte apoptosis, Ku expression, and myocardial fibrosis. In contrast, D2 mice exhibited a progressive recovery in cardiac function, which was indistinguishable from saline-treated animals by 9 weeks following the last DOX treatment. Improved cardiac function was accompanied by reductions in the levels of late stage cardiomyocyte apoptosis, Ku expression, and myocardial fibrosis. Conclusion These data suggest that cardiomyocyte cell cycle activity can promote recovery of cardiac function and preserve cardiac structure following DOX treatment. [ABSTRACT FROM AUTHOR]