Search

Heart failure is often the consequence of insufficient cardiac regeneration. Neonatal mice retain a certain capability of myocardial regeneration until postnatal day (P)7, although the underlying transcriptional mechanisms remain largely unknown. We demonstrate here that cardiac abundance of the transcription factor GATA4 was high at P1, but became strongly reduced at P7 in parallel with loss of regenerative capacity. Reconstitution of cardiac GATA4 levels by adenoviral gene transfer markedly improved cardiac regeneration after cryoinjury at P7. In contrast, the myocardial scar was larger in cardiomyocyte-specific Gata4 knockout ( CM-G4- KO) mice after cryoinjury at P0, indicative of impaired regeneration, which was accompanied by reduced cardiomyocyte proliferation and reduced myocardial angiogenesis in CM-G4- KO mice. Cardiomyocyte proliferation was also diminished in cardiac explants from CM-G4- KO mice and in isolated cardiomyocytes with reduced GATA4 expression. Mechanistically, decreased GATA4 levels caused the downregulation of several pro-regenerative genes (among them interleukin-13, Il13) in the myocardium. Interestingly, systemic administration of IL-13 rescued defective heart regeneration in CM-G4- KO mice and could be evaluated as therapeutic strategy in the future. [ABSTRACT FROM AUTHOR]

R3726 --> 713.12 --> Doxorubicin (DOX), an extremely effective and wide‐spectrum antineoplastic anthracycline, has been known for its notorious adverse effect of dose‐dependent dilated cardiotoxicity that culminates in heart failure. The current approach for reducing DOX‐induced cardiotoxicity is to limit the overall cumulative dose of the drug, but at the expense of narrowing the therapeutic window for cancer treatment. Therefore, it is imperative to identify new strategies to protect against DOX‐induced heart damage without compromising its antineoplastic activity. DOX cardiotoxicity is closely associated with mitochondrial injury which is characterized by an early loss of mitochondrial membrane potential followed by dysregulation of mitochondrial quality control mechanisms including mitophagy, a process through which injured mitochondria are degraded by the autophagic pathway. Mitophagy is generally believed to play protective roles under various normal and disease conditions. However, evidence also suggests that mitophagy can become detrimental, leading to cell death under certain conditions. The effect of DOX on mitophagy has been assessed previously, but neither mitophagy activity nor its functional role in DOX cardiotoxicity has been clearly defined. Parkin and FUNDC1 are two well‐established positive regulators of mitophagy. Knockdown of Parkin diminished DOX‐induced cell death, while overexpression of Parkin had the opposite effects, suggesting that DOX cardiotoxicity was mediated, at least in part, by accelerated mitophagy through a Parkin‐dependent pathway. However, the role of FUNDC1‐mediated mitophagy in DOX cardiotoxicity remains unclear. In this study, we investigated the functional role of FUNDC1 in DOX‐induced cardiotoxicity using both FUNDC1 knockout (KO) and transgenic (TG) mice. We hypothesized that knockout of FUNDC1 would alleviate DOX‐induced cardiotoxicity while overexpression of FUNDC1 would exacerbate DOX cardiotoxicity. DOX‐induced cardiac injury was examined and compared with WT and FUNDC1 KO (FKO) or FUNDC1 transgenic (FTG) mice. The Fractional Shortening (FS) was measured by echocardiography. Serum LDH activity and cardiac troponin‐I (cTnI) levels were measured and used as indicators of cardiac tissue damage. For the mitophagy flux assay, mice were treated with lysosomal proteasome inhibitors (25mg/kg pepA and 5mg/kg E64d) for 4 hours and the heart tissues were collected for Western blot analyses. Knockout of FUNDC1 reduced mitophagy in the mouse heart, while overexpression of FUNDC1 accelerated mitophagy flux, confirming FUNDC1 as a positive regulator of mitophagy. Knockout of FUNDC1 attenuated DOX‐induced cardiac functional impairment as shown by improved fractional shortening (FS), supporting the conclusion that FUNDC1‐dependent mitophagy may mediate DOX cardiotoxicity. Surprisingly, however, overexpression of FUNDC1 also alleviated DOX‐induced cardiac injury, suggesting that FUNDC1 may function independently of mitophagy in the maintenance of cardiac function. [ABSTRACT FROM AUTHOR]

The c-Jun N-terminal kinase (JNK) branch of the mitogen-activated protein kinase (MAPK) signaling pathway regulates cellular differentiation, stress responsiveness and apoptosis in multicellular eukaryotic organisms. Here we investigated the functional importance of JNK signaling in regulating differentiated cellular growth in the post-mitotic myocardium. JNK1/2 gene-targeted mice and transgenic mice expressing dominant negative JNK1/2 were determined to have enhanced myocardial growth following stress stimulation or with normal aging. A mechanism underlying this effect was suggested by the observation that JNK directly regulated nuclear factor of activated T-cell (NFAT) activation in culture and in transgenic mice containing an NFAT-dependent luciferase reporter. Moreover, calcineurin Aβ gene targeting abrogated the pro-growth effects associated with JNK inhibition in the heart, while expression of an MKK7-JNK1 fusion protein in the heart partially reduced calcineurin-mediated cardiac hypertrophy. Collectively, these results indicate that JNK signaling antagonizes the differentiated growth response of the myocardium through direct cross-talk with the calcineurin-NFAT pathway. These results also suggest that myocardial JNK activation is primarily dedicated to modulating calcineurin-NFAT signaling in the regulation of differentiated heart growth. [ABSTRACT FROM AUTHOR]