Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor-beta/bone morphogenetic protein (TGF-beta/BMP) signaling pathway is essential for embryonic and postnatal heart development and remodeling. The intracellular factor Smad4 plays a pivotal role in mediating TGF-beta/BMP signal transduction in the nucleus. To examine the function of Smad4 in embryonic cardiac development during mid-gestation, we specifically deleted the Smad4 gene in embryonic cardiomyocytes using the Cre-LoxP system. Deletion of Smad4 as early as E9.5, led to embryonic lethality between E12.5 and E15.5, and embryos exhibited severe morphological defects in the heart, including a thin compact layer, disorganized trabeculae, and ventricular septum defects (VSD). Smad4 deletion also led to a dramatic decrease in cardiomyocyte proliferation accompanied by downregulation of contractile protein-encoding genes such as alpha-myosin heavy chain, beta-myosin heavy chain, ventricular myosin light chain 2, and alpha-cardiac actin. In addition, deletion of Smad4 resulted in perturbation of TGF-beta/BMP ligand expression and signaling, and defects in expression of several cardiac transcription factor genes such as Nkx2.5, GATA4, and MEF2c. These results provide direct genetic evidences that Smad4 is essential for regulating cardiomyocyte proliferation and differentiation during murine cardiogenesis, and provides new insights into potential causes of congenital heart disease.
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PMID:Essential role of Smad4 in maintaining cardiomyocyte proliferation during murine embryonic heart development. 1786 37

Although bone marrow-derived mesenchymal stromal cells (MSCs) may be beneficial in treating heart disease, their ability to transdifferentiate into functional cardiomyocytes remains unclear. Here, bone marrow-derived MSCs from adult female transgenic mice expressing green fluorescent protein (GFP) under the control of the cardiac-specific alpha-myosin heavy chain promoter were cocultured with male rat embryonic cardiomyocytes (rCMs) for 5-15 days. After 5 days in coculture, 6.3% of MSCs became GFP(+) and stained positively for the sarcomeric proteins troponin I and alpha-actinin. The mRNA expression for selected cardiac-specific genes (atrial natriuretic factor, Nkx2.5, and alpha-cardiac actin) in MSCs peaked after 5 days in coculture and declined thereafter. Despite clear evidence for the expression of cardiac genes, GFP(+) MSCs did not generate action potentials or display ionic currents typical of cardiomyocytes, suggesting retention of a stromal cell phenotype. Detailed immunophenotyping of GFP(+) MSCs demonstrated expression of all antigens used to characterize MSCs, as well as the acquisition of additional markers of cardiomyocytes with the phenotype CD45(-)-CD34(+)-CD73(+)-CD105(+)-CD90(+)-CD44(+)-SDF1(+)-CD134L(+)-collagen type IV(+)-vimentin(+)-troponin T(+)-troponin I(+)-alpha-actinin(+)-connexin 43(+). Although cell fusion between rCMs and MSCs was detectable, the very low frequency (0.7%) could not account for the phenotype of the GFP(+) MSCs. In conclusion, we have identified an MSC population displaying plasticity toward the cardiomyocyte lineage while retaining mesenchymal stromal cell properties, including a nonexcitable electrophysiological phenotype. The demonstration of an MSC population coexpressing cardiac and stromal cell markers may explain conflicting results in the literature and indicates the need to better understand the effects of MSCs on myocardial injury. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Bone marrow-derived mesenchymal stromal cells express cardiac-specific markers, retain the stromal phenotype, and do not become functional cardiomyocytes in vitro. 1868 94