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Increasing angiogenesis has long been considered a therapeutic target for improving heart function after injury such as acute myocardial infarction. However, gene, protein and cell therapies to increase microvascularization have not been successful, most likely because the studies failed to achieve regulated and concerted expression of pro-angiogenic and angiostatic factors needed to produce functional microvasculature. Here, we report that the transcription factor RBPJ is a homoeostatic repressor of multiple pro-angiogenic and angiostatic factor genes in cardiomyocytes. RBPJ controls angiogenic factor gene expression independently of Notch by antagonizing the activity of hypoxia-inducible factors (HIFs). In contrast to previous strategies, the cardiomyocyte-specific deletion of Rbpj increased microvascularization of the heart without adversely affecting cardiac structure or function even into old age. Furthermore, the loss of RBPJ in cardiomyocytes increased hypoxia tolerance, improved heart function and decreased pathological remodelling after myocardial infarction, suggesting that inhibiting RBPJ might be therapeutic for ischaemic injury.

Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues. Here we report that genetic loss of APJ, a G-protein-coupled receptor, confers resistance to chronic pressure overload by markedly reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin (the endogenous APJ ligand) remain sensitive, suggesting an apelin-independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechanosensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate Gαi and elicits a protective response, stretch signals in an APJ-dependent, G-protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of β-arrestins or by pharmacological doses of apelin acting through Gαi. Taken together, our data indicate that APJ is a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy.

The circulating, adipocyte-secreted hormone adiponectin (APN) exerts protective effects on the heart under stress conditions. The receptors binding APN to cardiac tissue, however, have remained elusive. Here, we report that the glycosyl phosphatidylinositol-anchored cell surface glycoprotein T-cadherin (encoded by Cdh13) protects against cardiac stress through its association with APN in mice. We observed extensive colocalization of T-cadherin and APN on cardiomyocytes in vivo. In T-cadherin-deficient mice, APN failed to associate with cardiac tissue, and its levels dramatically increased in the circulation. Pressure overload stress resulted in exacerbated cardiac hypertrophy in T-cadherin-null mice and paralleled corresponding defects in mice lacking APN. During ischemia-reperfusion injury, the absence of T-cadherin increased infarct size similar to that in APN-null mice. Myocardial AMPK is a major downstream protective signaling target of APN. In both cardiac hypertrophy and ischemia-reperfusion models, T-cadherin was necessary for APN-dependent AMPK phosphorylation. In APN-null mice, recombinant adenovirus-expressed APN reduced exaggerated hypertrophy and infarct size and restored AMPK phosphorylation as previously reported. In contrast, rescue was ineffective in mice lacking T-cadherin in addition to APN. These data suggest that T-cadherin protects from stressinduced pathological cardiac remodeling by binding APN and activating its cardioprotective functions., Introduction Acute or chronic stress to the heart leads to pathological remodeling that can result in heart failure. Acute myocardial ischemia is caused by insufficient coronary blood supply of the [...]

Studies reveal that disruption of the podosome adaptor protein TKS4 causes the skeletal dysplasia, eye and cardiac abnormalities of the autosomal-recessive disorder Frank-Ter Haar syndrome (FTHS). An analysis identifies homozygous mutations of the SH3PXD2B gene which encodes the TKS4 protein as the cause of the disorder.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2008.07.038 Byline: Somyoth Sridurongrit (a)(b), Jonas Larsson (c), Robert Schwartz (d), Pilar Ruiz-Lozano (e), Vesa Kaartinen (a)(b) Keywords: Tgf-[beta] signaling; Epicardium; Endocardium; Heart development Abstract: Trophic factors secreted both from the endocardium and epicardium regulate appropriate growth of the myocardium during cardiac development. Epicardially-derived cells play also a key role in development of the coronary vasculature. This process involves transformation of epithelial (epicardial) cells to mesenchymal cells (EMT). Similarly, a subset of endocardial cells undergoes EMT to form the mesenchyme of endocardial cushions, which function as primordia for developing valves and septa. While it has been suggested that transforming growth factor-[beta]s (Tgf-[beta]) play an important role in induction of EMT in the avian epi- and endocardium, the function of Tgf-[beta]s in corresponding mammalian tissues is still poorly understood. In this study, we have ablated the Tgf-[beta] type I receptor Alk5 in endo-, myo- and epicardial lineages using the Tie2-Cre, Nkx2.5-Cre, and Gata5-Cre driver lines, respectively. We show that while Alk5-mediated signaling does not play a major role in the myocardium during mouse cardiac development, it is critically important in the endocardium for induction of EMT both in vitro and in vivo. Moreover, loss of epicardial Alk5-mediated signaling leads to disruption of cell-cell interactions between the epicardium and myocardium resulting in a thinned myocardium. Furthermore, epicardial cells lacking Alk5 fail to undergo Tgf-[beta]-induced EMT in vitro. Late term mutant embryos lacking epicardial Alk5 display defective formation of a smooth muscle cell layer around coronary arteries, and aberrant formation of capillary vessels in the myocardium suggesting that Alk5 is controlling vascular homeostasis during cardiogenesis. To conclude, Tgf-[beta] signaling via Alk5 is not required in myocardial cells during mammalian cardiac development, but plays an irreplaceable cell-autonomous role regulating cellular communication, differentiation and proliferation in endocardial and epicardial cells. Author Affiliation: (a) University of Michigan, Department of Biologic and Materials Sciences, Ann Arbor, MI 48109, USA (b) Developmental Biology Program, The Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA (c) Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund University Hospital, 221 84 Lund, Sweden (d) Texas A&M Health Science Center, Houston, TX 77035, USA (e) The Burnham Institute for Medical Research, La Jolla, CA 92037, USA Article History: Received 22 February 2008; Revised 22 July 2008; Accepted 31 July 2008

We have previously identified several members of the Wnt/ [beta]-catenin pathway that are differentially expressed in a mouse model with deficient coronary vessel formation. Systemic ablation of [beta]-catenin expression affects mouse development at gastrulation with failure of both mesoderm development and axis formation. To circumvent this early embryonic lethality and study the specific role of [beta]-catenin in coronary arteriogenesis, we have generated conditional [beta]-catenin-deletion mutant animals in the proepicardium by interbreeding with a Cre-expressing mouse that targets coronary progenitor cells in the proepicardium and its derivatives. Ablation of [beta]-catenin in the proepicardium results in lethality between embryonic day 15 and birth. Mutant mice display impaired coronary artery formation, whereas the venous system and microvasculature are normal. Analysis of proepicardial [beta]-catenin mutant cells in the context of an epicardial tracer mouse reveals that the formation of the proepicardium, the migration of proepicardial cells to the heart, and the formation of the primitive epicardium are unaffected. However, subsequent processes of epicardial development are dramatically impaired in epicardial-[beta]-catenin mutant mice, including failed expansion of the sub-epicardial space, blunted invasion of the myocardium, and impaired differentiation of epicardium-derived mesenchymal cells into coronary smooth muscle cells. Our data demonstrate a functional role of the epicardial [beta]-catenin pathway in coronary arteriogenesis. cardiovascular development | smooth muscle | proepicardium | Wnt signaling

Author(s): Alessandra Care [1, 11]; Daniele Catalucci [2, 3, 11]; Federica Felicetti [1]; Desiree Bonci [1]; Antonio Addario [1]; Paolo Gallo [3, 4]; Marie-Louise Bang [2, 3]; Patrizia Segnalini [1]; [...]

The role of HF-1b gene from ventricular and neural crest cells lineages in the development of cardiac conduction system in vertebrate embryos is studied.

Vitamin A signals play critical roles during embryonic development. In particular, heart morphogenesis depends on vitamin A signals mediated by the retinoid X receptor [alpha] (RXR [alpha]), as the systemic mutation of this receptor results in thinning of the myocardium and embryonic lethality. However, the molecular and cellular mechanisms controlled by RXR [alpha] signaling in this process are unclear, because a myocardium-restricted RXR [alpha] mutation does not perturb heart morphogenesis. Here, we analyze a series of tissue-restricted mutations of the RXR [alpha] gene in the cardiac neural crest, endothelial, and epicardial lineages, and we show that RXR [alpha] signaling in the epicardium is required for proper cardiac morphogenesis. Moreover, we detect an additional phenotype of defective coronary arteriogenesis associated with RXR [alpha] deficiency and identify a retinoid-dependent Wnt signaling pathway that cooperates in epicardial epithelial-to-mesenchymal transformation. coronary vessels | epicardium | retinoids | wnt | FGF

Research has been conducted on cell type-specific molecular mechanisms. Results demonstrate that bicoid-related transcription factor Pitx2 is induced by Wnt/Dvl/beta-catenin pathway and is required for cell-type-specific proliferation via growth-regulating gene activation.

Research demonstrates that the HF-1b transcription factor of cardiac conduction system and ventricular myocytes play a role in the sudden cardiac death in humans. Data reveal that the cardiovascular arrest is due to cardiac arrhythmogenesis brought about by a decrease and mislocalization of connexins and defects in the formation of ventricular Purkinje fibers.