Targeting calcineurin induces cardiomyocyte proliferation in adult mice.

The mammalian neonatal heart can regenerate for 1 week after birth, after which, the majority of cardiomyocytes exit the cell cycle. Recent studies demonstrated that calcineurin mediates cell-cycle arrest of postnatal cardiomyocytes, partly through induction of nuclear translocation of the transcription factor Hoxb13 (a cofactor of Meis1). Here we show that inducible cardiomyocyte-specific deletion of calcineurin B1 in adult cardiomyocytes markedly decreases cardiomyocyte size and promotes mitotic entry, resulting in increased total cardiomyocyte number and improved left ventricular (LV) systolic function after myocardial infarction (MI).

A calcineurin-Hoxb13 axis regulates growth mode of mammalian cardiomyocytes.

A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting cardiomyocytes and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal cardiomyocytes.

Hypoxia induces heart regeneration in adult mice.

The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the lasting and severe effects of cardiomyopathy. Recently, it has become clear that the mammalian heart is not a post-mitotic organ. For example, the neonatal heart is capable of regenerating lost myocardium, and the adult heart is capable of modest self-renewal.

Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart.

Although the adult mammalian heart is incapable of meaningful functional recovery following substantial cardiomyocyte loss, it is now clear that modest cardiomyocyte turnover occurs in adult mouse and human hearts, mediated primarily by proliferation of pre-existing cardiomyocytes. However, fate mapping of these cycling cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers. In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia-inducible factor 1 alpha (Hif-1α) subunit is critical for their maintenance and function.

Human ventricular unloading induces cardiomyocyte proliferation.

Background: The adult mammalian heart is incapable of meaningful regeneration after substantial cardiomyocyte loss, primarily due to the inability of adult cardiomyocytes to divide. Our group recently showed that mitochondria-mediated oxidative DNA damage is an important regulator of postnatal cardiomyocyte cell cycle arrest. However, it is not known whether mechanical load also plays a role in this process.

Redox signaling in cardiac renewal.

Significance: Utilizing oxygen (O2) through mitochondrial oxidative phosphorylation enables organisms to generate adenosine triphosphate (ATP) with a higher efficiency than glycolysis, but it results in increased reactive oxygen species production from mitochondria, which can result in stem cell dysfunction and senescence.

Recent Advances: In the postnatal organism, the hematopoietic system represents a classic example of the role of stem cells in cellular turnover and regeneration. However, in other organs such as the heart, both the degree and source of cellular turnover have been heavily contested.

Cytoglobin modulates myogenic progenitor cell viability and muscle regeneration.

Mammalian skeletal muscle can remodel, repair, and regenerate itself by mobilizing satellite cells, a resident population of myogenic progenitor cells. Muscle injury and subsequent activation of myogenic progenitor cells is associated with oxidative stress. Cytoglobin is a hemoprotein expressed in response to oxidative stress in a variety of tissues, including striated muscle.

Synthesis and structure-affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes.

Efforts to develop ligands that distinguish between clinically relevant 5-HT2A and 5-HT2C serotonin receptor subtypes have been challenging, because their sequences have high homology. Previous studies reported that a novel aplysinopsin belonging to a chemical class of natural products isolated from a marine sponge was selective for the 5-HT2C over the 5-HT2A receptor subtype. Our goal was to explore the 5-HT2A/2C receptor structure-affinity relationships of derivatives based on the aplysinopsin natural product pharmacophore.

Mechanism of methoxide ion substitution in the z and e isomers of o-methylbenzohydroximoyl halides.

Kinetics and stereochemical studies have been carried out on the reactions of the Z and E isomers of O-methylbenzohydroximoyl halides [1Z and 1E, ArC(X)=NOCH(3)] with sodium methoxide in 9:1 DMSO-methanol. The reactions of methoxide ion with hydroximoyl fluorides (X = F) are stereospecific. The reaction with 1Z (X = F) gives only the Z substitution product (1Z, X =OCH(3)).