Circulation research
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Circulation research · Jan 2007
Bone marrow Oct3/4+ cells differentiate into cardiac myocytes via age-dependent paracrine mechanisms.
The mechanisms that govern the capacity of the bone marrow stem cells to generate cardiac myocytes are still unknown. Herein we demonstrate that the cardiomyogenic potential of bone marrow-derived Oct3/4(+)/cKit(+/-)/CXCR4(+/-)/CD34(-)/Sca1(-) cells is governed by age-dependent paracrine/juxtacrine platelet-derived growth factor (PDGF) pathways. Specifically, bone marrow cell cultures from both 3- and 18-month-old mice formed aggregates of Oct3/4(+) cells circumscribed by PDGFRalpha(+)/Oct3/4(-)/Sca1(+) cells. ⋯ Importantly, supplementation with PDGF-AB specifically restored the cardiac differentiation capacity of the old bone marrow cells. Together these results demonstrate that, regardless of age, the bone marrow niche contains Oct3/4 stem cells that are capable of differentiating into cardiac myocytes. Moreover, this differentiation is governed by age-dependent PDGF-AB-mediated paracrine/juxtacrine pathways that may be essential in the translation of bone marrow cell-mediated cardiomyogenesis.
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Circulation research · Nov 2006
Deletion of microsomal prostaglandin E synthase-1 increases sensitivity to salt loading and angiotensin II infusion.
Microsomal prostaglandin E synthase-1 (mPGES-1), a membrane-associated protein, is critically involved in the inflammatory response and may be involved in physiological processes as well. The present study examined the role of mPGES-1 in regulation of sodium balance and blood pressure in the settings of salt loading and angiotensin II infusion. mPGES-1 -/- mice developed severe and progressive hypertension associated with an inappropriate increase in sodium balance when fed a high-salt diet. These mice exhibited a significantly impaired ability to excrete an acute enteral load of NaCl. ⋯ These findings have revealed a mPGES-1/prostaglandin E(2)/NO/cGMP pathway that appears to be critically important for salt adaptation. In addition, we provide evidence that mPGES-1 deficiency sensitized the hypertensive effect of angiotensin II. Overall, this study has characterized the natriuretic and antihypertensive role of mPGES-1 that likely contributes to blood pressure homeostasis.
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Circulation research · Nov 2006
ATP release from activated neutrophils occurs via connexin 43 and modulates adenosine-dependent endothelial cell function.
Extracellular ATP liberated during hypoxia and inflammation can either signal directly on purinergic receptors or can activate adenosine receptors following phosphohydrolysis to adenosine. Given the association of polymorphonuclear leukocytes (PMNs) with adenine-nucleotide/nucleoside signaling in the inflammatory milieu, we hypothesized that PMNs are a source of extracellular ATP. Initial studies using high-performance liquid chromatography and luminometric ATP detection assays revealed that PMNs release ATP through activation-dependent pathways. ⋯ These studies showed that PMN ATP release occurs through connexin 43 (Cx43) hemichannels in a protein/phosphatase-A-dependent manner. Findings in human PMNs were confirmed in PMNs derived from induced Cx43(-/-) mice, whereby activated PMNs release less than 15% of ATP relative to littermate controls, whereas Cx43 heterozygote PMNs were intermediate in their capacity for ATP release (P<0.01). Taken together, our results identify a previously unappreciated role for Cx43 in activated PMN ATP release, therein contributing to the innate metabolic control of the inflammatory milieu.
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Circulation research · Oct 2006
Increases in mitochondrial reactive oxygen species trigger hypoxia-induced calcium responses in pulmonary artery smooth muscle cells.
Mitochondria have been implicated as a potential site of O(2) sensing underlying hypoxic pulmonary vasoconstriction (HPV), but 2 disparate models have been proposed to explain their reaction to hypoxia. One model proposes that hypoxia-induced increases in mitochondrial reactive oxygen species (ROS) generation activate HPV through an oxidant-signaling pathway, whereas the other proposes that HPV is a result of decreased oxidant signaling. In an attempt to resolve this debate, we use a novel, ratiometric, redox-sensitive fluorescence resonance energy transfer (HSP-FRET) probe, in concert with measurements of reduced/oxidized glutathione (GSH/GSSG), to assess cytosolic redox responses in cultured pulmonary artery smooth muscle cells (PASMCs). ⋯ The mitochondrial inhibitor myxothiazol attenuated the hypoxia-induced changes in the ROS signaling and [Ca(2+)](i), whereas cyanide augmented the increase in [Ca(2+)](i). Finally, simultaneous measurement of ROS and Ca(2+) signaling in the same cell revealed that the initial increase in these 2 signals could not be distinguished temporally. These results demonstrate that hypoxia triggers increases in PASMC [Ca(2+)](i) by augmenting ROS signaling from the mitochondria.