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Circulation research [journal]
- Macrophage Migration Inhibitory Factor (MIF) Limits Activation-Induced Apoptosis of Platelets via CXCR7-dependent Akt Signaling. [JOURNAL ARTICLE]
- Circ Res 2014 Sep 29.
Rationale: Macrophage migration inhibitory factor (MIF) is released upon platelet activation. Circulating MIF could potentially regulate platelets and thereby platelet-mediated inflammatory and regenerative mechanisms. However the effect of MIF on platelets is unknown. Objective: The current study evaluated MIF in regulating platelet survival and thrombotic potential. Methods and Results: MIF interacted with CXCR4-CXCR7 on platelets, defining CXCR7 as a hitherto unrecognized receptor for MIF on platelets. MIF internalized CXCR4, but unlike CXCL12 (SDF-1α), it did not phosphorylate Erk1/2 following CXCR4 ligation due to the lack of CD74 and failed in subsequent CXCR7 externalization. MIF did not alter the activation status of platelets. However, MIF rescued platelets from activation and BH3 mimetic-ABT-737-induced apoptosis in vitro via CXCR7 and enhanced circulating platelet survival when administered in vivo. The anti-apoptotic effect of MIF was absent in Cxcr7(-/-) murine embryonic cells but pronounced in CXCR7 transfected MDCK cells. This pro-survival effect was attributed to the MIF-CXCR7-initiated PI3K-Akt pathway. MIF induced CXCR7-Akt-dependent phosphorylation of BCL-2 antagonist of cell death (BAD) both in vitro and in vivo. Consequentially, MIF failed to rescue Akt(-/-) platelets from thrombin induced apoptosis when challenged ex vivo, also in prolonging platelet survival and in inducing BAD phosphorylation among Akt(-/-) mice in vivo. MIF reduced thrombus formation under arterial flow conditions in vitro and retarded thrombotic occlusion following FeCl3-induced arterial injury in vivo, an effect mediated through CXCR7. Conclusions: MIF interaction with CXCR7 modulates platelet survival and thrombotic potential both in vitro and in vivo, and thus could regulate thrombosis and inflammation.
- Dan roden: learn, apply, evolve. [Journal Article]
- Circ Res 2014 Sep 26; 115(8):693-5.
- Muscling up the heart: a preadolescent cardiomyocyte proliferation contributes to heart growth. [Journal Article]
- Circ Res 2014 Sep 26; 115(8):690-2.
- SUMOylation: A Novel Protein Quality Control Modifier in the Heart. [Editorial]
- Circ Res 2014 Sep 26; 115(8):686-9.
- Fox(y) Regulators of VEGF Receptors. [Editorial]
- Circ Res 2014 Sep 26; 115(8):683-5.
- 14q32 miRNA Cluster Takes Center Stage in Neovascularization. [Editorial]
- Circ Res 2014 Sep 26; 115(8):680-2.
- Pi3kcb Links Hippo-YAP and PI3K-AKT Signaling Pathways to Promote Cardiomyocyte Proliferation and Survival. [JOURNAL ARTICLE]
- Circ Res 2014 Sep 23.
Rationale: YAP, the nuclear effector of Hippo signaling, regulates cellular growth and survival in multiple organs, including the heart, by interacting with TEAD sequence specific DNA-binding proteins. Recent studies showed that YAP stimulates cardiomyocyte proliferation and survival. However, the direct transcriptional targets through which YAP exerts its effects are poorly defined. Objective: To identify direct YAP targets that mediate its mitogenic and anti-apoptotic effects in the heart. Methods and Results: We identified direct YAP targets by combining differential gene expression analysis in YAP gain- and loss-of-function with genome-wide identification of YAP bound loci using chromatin immunoprecipitation and high throughput sequencing. This screen identified Pik3cb, encoding p110β, a catalytic subunit of phosphoinositol-3-kinase (PI3K), as a candidate YAP effector that promotes cardiomyocyte proliferation and survival. YAP and TEAD occupied a conserved enhancer within the first intron of Pik3cb, and this enhancer drove YAP-dependent reporter gene expression. Yap gain- and loss-of-function studies indicated that YAP is necessary and sufficient to activate the PI3K-Akt pathway. Like Yap, Pik3cb gain-of-function stimulated cardiomyocyte proliferation, and Pik3cb knockdown dampened YAP mitogenic activity. Reciprocally, impaired heart function in Yap loss-of-function was significantly rescued by AAV-mediated Pik3cb expression. Conclusions: Pik3cb is a crucial direct target of YAP, through which the YAP activates PI3K-AKT pathway and regulates cardiomyocyte proliferation and survival.
- Hyperphosphorylation of RyRs Underlies Triggered Activity in Transgenic Rabbit Model of LQT2 Syndrome. [JOURNAL ARTICLE]
- Circ Res 2014 Sep 23.
Rationale: Loss-of function mutations in HERG potassium channels underlie long QT syndrome (LQTS) type 2 (LQT2), and are associated with fatal ventricular tachyarrhythmia. Previously, most studies focused on plasmamembrane-related pathways involved in arrhythmogenesis in LQTS, while pro-arrhythmic changes in intracellular Ca2+ handling remained unexplored. Objective: We investigated the remodeling of Ca(2+) homeostasis in ventricular cardiomyocytes derived from transgenic rabbit model of LQT2 in order to determine whether these changes contribute to triggered activity in the form of early afterdepolarizations (EADs). Methods and Results: Confocal Ca(2+) imaging revealed decrease in amplitude of Ca(2+) transients and SR Ca(2+) content in LQT2 myocytes. Experiments using SR-entrapped Ca(2+) indicator demonstrated enhanced RyR-mediated SR Ca(2+) leak in LQT2 cells. Western blot analyses showed increased phosphorylation of RyR in LQT2 myocytes vs. controls. Co-immunoprecipitation experiments demonstrated loss of protein phosphatases type 1 and type 2 from the RyR complex. Stimulation of LQT2 cells with β-adrenergic agonist isoproterenol resulted in prolongation of the plateau of action potentials accompanied by aberrant Ca(2+) releases and EADs, which were abolished by inhibition of CaMKII. Computer simulations showed that late aberrant Ca(2+) releases caused by RyR hyperactivity promote EADs and underlie the enhanced triggered activity through increased forward mode of NCX1. Conclusions: Hyperactive, hyperphosphorylated RyRs due to reduced local phosphatase activity enhance triggered activity in LQT2 syndrome. EADs are promoted by aberrant RyR-mediated Ca(2+) releases that are present despite a reduction of sarcoplasmic reticulum (SR) content. Those releases increase forward mode NCX1, thereby slowing repolarization and enabling L-type Ca(2+) current reactivation.
- Tbx5 is Required for Avian and Mammalian Epicardial Formation and Coronary Vasculogenesis. [JOURNAL ARTICLE]
- Circ Res 2014 Sep 22.
Rationale: Holt-Oram syndrome (HOS) is an autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene. Overexpression of Tbx5 in the chick proepicardial organ (PEO) impaired coronary blood vessel formation. However, the potential activity of Tbx5 in the epicardium itself, and Tbx5's role in mammalian coronary vasculogenesis, remains largely unknown. Objective: To evaluate the consequences of altered Tbx5 gene dosage during PEO and epicardial development in the embryonic chick and mouse. Methods and Results: Retroviral-mediated knockdown or upregulation of Tbx5 expression in the embryonic chick PEO as well as proepicardial-specific deletion of Tbx5 in the embryonic mouse (Tbx5(epi-/-)) impaired normal PEO cell development, inhibited epicardial and coronary blood vessel formation and altered developmental gene expression. The generation of epicardial-derived cells (EPDCs) and their migration into the myocardium was impaired between embryonic day (E) 13.5-15.5 in mutant hearts due to delayed epicardial attachment to the myocardium and subepicardial accumulation of EPDCs. This caused defective coronary vasculogenesis associated with impaired vascular smooth muscle cell recruitment, and reduced invasion of cardiac fibroblasts and endothelial cells into myocardium. In contrast to wildtype hearts that exhibited an elaborate ventricular vascular network, Tbx5(epi-/-) hearts displayed a marked decrease in vascular density that was associated with myocardial hypoxia as exemplified by HIF1α upregulation and increased binding of Hypoxyprobe-1. Tbx5(epi-/-) mice with such myocardial hypoxia exhibited reduced exercise capacity compared to wildtype mice. Conclusions: Our findings support a conserved Tbx5 dose-dependent requirement for both proepicardial and epicardial progenitor cell development in chick and mouse coronary vascular formation.