Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload

Abstract

and ClueGO (54) and significantly regulated genes (cutoff adjusted P value < 0.05) of the transcriptomes of D2-TAC mice compared with D2-Shunt mice. The analysis is based on the following databases: GO biological function, GO cellular component, GO immune system process, GO molecular function, KEGG, REACTOME, and WikiPathways using GO Term Fusion and showing pathways with a P value of less than 0.05, a Kappa score of 0.4, and a minimum of 20 genes representing at least 5% of all genes of the pathway.Statistics. Results are expressed as mean ± SEM. Survival was tested with the log-rank (Mantel-Cox) test. Multiple group comparisons were performed by 2-way analysis of variance (ANOVA) followed by the Bonferroni procedure for comparison of means. Comparisons between 2 groups were performed using the unpaired 2-tailed Student's t test. All tests were 2-sided. Data were considered statistically significant at P less than 0.05.Study approval. The investigation conformed to the Guide for the Care and Use of Laboratory Animals (NIH publication number 85-23, revised 1996). The study was approved by the Lower Saxony State Office for Consumer Protection and Food Safety (G64/08 and 15/1860).

Targeted expression of cyclin D2 ameliorates late stage anthracycline cardiotoxicity

“…S-phase cardiomyocyte nuclei were readily identified by the presence of silver grains overlaying blue X-GAL reaction product ( Figure 2B). In agreement with previous studies, 15,16,18 saline-treated D2 mice had markedly elevated levels of cardiomyocyte S-phase activity when compared with saline-treated WT mice ( Figure 2C). DOX treatment resulted in a five-fold decrease in S-phase activity in the D2 mice when assessed in the acute stage.…”

“…15 Previous studies have shown that enhanced cardiomyocyte renewal rates in D2 mice are associated with progressive structural and functional recovery following myocardial infarction, 15,17,18 cytokineinduced atrial fibrosis, 19 and chronic pressure overload. 16 Here, we show that the enhanced level of cardiomyocyte renewal in D2 mice is associated with progressive recovery from anthracycline-induced heart failure.…”

“…We have previously shown 15,16 that D2 mice exhibit sustained cyclin D2 expression for up to 12 months of age (the latest time point tested). Transgene expression is accompanied with cardiomyocyte cell cycle activity, as evidenced by the presence of elevated levels of cardiomyocyte S-phase activity, elevated levels of cardiomyocyte phosphorylated histone H3 immune reactivity, and increased cardiomyocyte numbers in postnatal hearts.…”

“…These animals exhibit sustained increases in postnatal cardiomyocyte S-phase activity, phosphorylated histone H3 expression, and cardiomyocyte division (the latter evidenced by increased cell numbers in dispersed cell preparations) when compared with their wild type (WT) littermates. 15,16 Interestingly, cardiomyocyte nucleation patterns are normal in these mice. 15 Previous studies have shown that enhanced cardiomyocyte renewal rates in D2 mice are associated with progressive structural and functional recovery following myocardial infarction, 15,17,18 cytokineinduced atrial fibrosis, 19 and chronic pressure overload.…”

Induction of cardiomyocyte proliferation and angiogenesis protects neonatal mice from pressure overload–associated maladaptation

“…The deleterious role of rapamycin stands in contrast with its beneficial effects during pressure overload in adult mice when no cardiomyocyte proliferation occurs and when it ameliorates cardiac dysfunction by blocking pathological cardiomyocyte hypertrophy (33). The adaptive role of cardiomyocyte proliferation during pressure overload is supported by the finding that myocardial overexpression of cyclin D2 promotes cardiomyocyte proliferation during TAC in adult mice, thereby upholding cardiac function and counteracting fibrosis, while at the same time limiting cardiac hypertrophy (34). We also observed in our study that the occurrence of cardiomyocyte proliferation prevented maladaptive cardiomyocyte hypertrophy, while in turn, inhibition of cardiomyocyte proliferation (due to the deletion of GATA4 or due to PTK787 treatment) led to cardiomyocyte hypertrophy and cardiac dysfunction.…”