BHLH Transcription Factor TCF21 Inhibits Myofibroblast Formation and Cardiac Fibrosis.

Background: TCF21 (transcription factor 21) is a bHLH (basic helix-loop-helix) protein required for the developmental specification of cardiac fibroblasts (CFs) from epicardial progenitor cells that surround the embryonic heart. In the adult heart, TCF21 is expressed in tissue-resident fibroblasts and is downregulated in response to injury or stimuli leading to myofibroblast differentiation. These findings led to the hypothesis that TCF21 regulates fibroblast differentiation in the adult mammalian heart to affect fibrosis.

gene deletion in mice reduces heart weight over time.

The ribosomal protein L3-like (RPL3L) is a heart and skeletal muscle-specific ribosomal protein and paralogue of the more ubiquitously expressed RPL3 protein. Mutations in the human gene are linked to childhood cardiomyopathy and age-related atrial fibrillation, yet the function of RPL3L in the mammalian heart remains unknown. Here, we observed that mouse cardiac ventricles express RPL3 at birth, where it is gradually replaced by RPL3L in adulthood but re-expressed with induction of hypertrophy in adults.

Thymosin β4 and prothymosin α promote cardiac regeneration post-ischaemic injury in mice.

Aims: The adult mammalian heart is a post-mitotic organ. Even in response to necrotic injuries, where regeneration would be essential to reinstate cardiac structure and function, only a minor percentage of cardiomyocytes undergo cytokinesis. The gene programme that promotes cell division within this population of cardiomyocytes is not fully understood.

An acute immune response underlies the benefit of cardiac stem cell therapy.

Clinical trials using adult stem cells to regenerate damaged heart tissue continue to this day, despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biological effect. The rationale for these cell therapy trials is derived from animal studies that show a modest but reproducible improvement in cardiac function in models of cardiac ischaemic injury. Here we examine the mechanistic basis for cell therapy in mice after ischaemia-reperfusion injury, and find that-although heart function is enhanced-it is not associated with the production of new cardiomyocytes.

Hippo signaling does it again: arbitrating cardiac fibroblast identity and activation.

The Hippo pathway is an evolutionarily conserved kinase cascade that is fundamental for tissue development, homeostasis, and regeneration. In the developing mammalian heart, Hippo signaling regulates cardiomyocyte numbers and organ size. While cardiomyocytes in the adult heart are largely postmitotic, Hippo deficiency can increase proliferation of these cells and affect cardiac regenerative capacity.

Cardiac Fibroblasts and the Extracellular Matrix in Regenerative and Nonregenerative Hearts.

During the postnatal period in mammals, the heart undergoes significant remodeling and cardiac cells progressively lose their embryonic characteristics. At the same time, notable changes in the extracellular matrix (ECM) composition occur with a reduction in the components considered facilitators of cellular proliferation, including fibronectin and periostin, and an increase in collagen fiber organization. Not much is known about the postnatal cardiac fibroblast which is responsible for producing the majority of the ECM, but during the days after birth, mammalian hearts can regenerate after injury with only a transient scar formation.

Role of the Aryl Hydrocarbon Receptor/ARNT/Cytochrome P450 System in Pulmonary Vascular Diseases.

Rationale: CYPs (cytochrome p450) are critically involved in the metabolism of xenobiotics and toxins. Given that pulmonary hypertension is strongly associated with environmental exposure, we hypothesize that CYPs play a role in the development and maintenance of pathological vascular remodeling.

Objective: We sought to identify key CYPs that could link drug or hormone metabolism to the development of pulmonary hypertension.

The serotonin transporter promotes a pathological estrogen metabolic pathway in pulmonary hypertension via cytochrome P450 1B1.

Pulmonary arterial hypertension (PAH) is a devastating vasculopathy that predominates in women and has been associated with dysregulated estrogen and serotonin signaling. Overexpression of the serotonin transporter (SERT(+)) in mice results in an estrogen-dependent development of pulmonary hypertension (PH). Estrogen metabolism by cytochrome P450 1B1 (CYP1B1) contributes to the pathogenesis of PAH, and serotonin can increase CYP1B1 expression in human pulmonary arterial smooth muscle cells (hPASMCs).