BackgroundNew therapeutic targets for cardiac hypertrophy, an independent risk factor for heart failure and death, are essential. HNO is a novel redox sibling of NO• attracting considerable attention for the treatment of cardiovascular disorders, eliciting cGMP-dependent vasodilatation yet cGMP-independent positive inotropy. The impact of HNO on cardiac hypertrophy (which is negatively regulated by cGMP) however has not been investigated.MethodsNeonatal rat cardiomyocytes were incubated with angiotensin II (Ang II) in the presence and absence of the HNO donor Angeli's salt (sodium trioxodinitrate) or B-type natriuretic peptide, BNP (all 1 µmol/L). Hypertrophic responses and its triggers, as well as cGMP signaling, were determined.ResultsWe now demonstrate that Angeli's salt inhibits Ang II-induced hypertrophic responses in cardiomyocytes, including increases in cardiomyocyte size, de novo protein synthesis and β-myosin heavy chain expression. Angeli's salt also suppresses Ang II induction of key triggers of the cardiomyocyte hypertrophic response, including NADPH oxidase (on both Nox2 expression and superoxide generation), as well as p38 mitogen-activated protein kinase (p38MAPK). The antihypertrophic, superoxide-suppressing and cGMP-elevating effects of Angeli's salt were mimicked by BNP. We also demonstrate that the effects of Angeli's salt are specifically mediated by HNO (with no role for NO• or nitrite), with subsequent activation of cardiomyocyte soluble guanylyl cyclase (sGC) and cGMP signaling (on both cGMP-dependent protein kinase, cGK-I and phosphorylation of vasodilator-stimulated phosphoprotein, VASP).ConclusionsOur results demonstrate that HNO prevents cardiomyocyte hypertrophy, and that cGMP-dependent NADPH oxidase suppression contributes to these antihypertrophic actions. HNO donors may thus represent innovative pharmacotherapy for cardiac hypertrophy.

Context:The pathogenic origin of preeclampsia is defective placental development (placentation) and function. Preeclampsia is not diagnosed until later in pregnancy, and reliable early detection is highly desirable. HtrA3 is a recently cloned gene with high expression during placentation in the mouse, rhesus monkey, and human.Objective: The present study examined the placental production and the serum profile of HtrA3 across gestation in women, the potential molecular mechanisms regulating HtrA3 production, and the association between maternal HtrA3 serum levels and preeclampsia. Methods:Immunohistochemistry determined HtrA3 expression pattern and cellular localization in first-, second-, and third-trimester placenta. The maternal serum HtrA3 levels were analyzed by Western blotting. The regulation of placental HtrA3 production and the secretion by oxygen tension was investigated in first-trimester placental explants and trophoblast cells.Results: Placental HtrA3 protein was maximally produced in the first trimester and then dramatically down-regulated, especially in the syncytiotrophoblast. HtrA3 was secreted into the maternal circulation with a serum profile reflecting placental production. Oxygen tension regulated HtrA3; low oxygen enhanced, whereas the transition from low to high oxygen decreased, HtrA3 protein production in syncytiotrophoblast. Maternal serum HtrA3 levels at approximately 13-14 wk of gestation were significantly higher in women who subsequently developed preeclampsia. It appeared that HtrA3 down-regulation was delayed in preeclamptic pregnancies. Conclusions:HtrA3 protein production is closely associated with changing in oxygen tension in the placenta. The decline in HtrA3 at the end of first trimester may reflect the placental low to high oxygen switch. Abnormally high levels of serum HtrA3 at approximately 13-14 wk of gestation is associated with preeclampsia. (J Clin Endocrinol Metab 96: 403-411, 2011) P reeclampsia is a serious disorder of human pregnancy affecting 5-10% of pregnant women (1). It contributes significantly to both maternal and fetal morbidity and mortality, accounting for about 18% of maternal and perinatal deaths in industrialized countries (2, 3). Preeclampsia is not diagnosed until it becomes clinically apparent late in pregnancy, at which time delivery is the only effective cure, often inflicting prematurity. The burden of preeclampsia thus also falls on the neonate because fetal survival rates inversely correlate with gestational age; survival rate for a baby born at 23 wk is less than 10% (4).

Defending cellular integrity against disturbances in intracellular concentrations of ATP ([ATP]i) is predicated upon coordinating the selection of substrates and their flux through metabolic pathways (metabolic signaling), ATP transfer from sites of production to utilization (energetic signaling), and the regulation of processes consuming energy (cell signaling). Nitric oxide (NO) and its receptor soluble guanylyl cyclase (sGC) are key mediators of cellular energetics and can regulate ATP supply and demand. However, mechanisms coordinating NO/sGC and energetic signaling remain undefined. Here, we demonstrate that sGC is a nucleotide sensor whose responsiveness to NO is regulated by intracellular ATP ([ATP]i). ATP inhibits purified sGC with a Ki predicting >60% inhibition of NO signaling in cells maintaining physiological [ATP]i. ATP inhibits sGC by interacting with an allosteric site that prefers ATP>GTP. Moreover, in RFL‐6 cells, alterations in [ATP]i are coupled to NO/sGC signaling. Indeed, oligomycin, an inhibitor of mitochondrial ATP synthase, reduced [ATP]i 48%, from 1.25 nmol to 0.65 nmol of ATP/mg protein, but increased [cGMP]i 45%, from 42 to 61 pmol/mg protein. Thus, [ATP]i serves as a “gain control” for NO signaling by sGC. At physiological [ATP]i, NO signaling by sGC is repressed, while insults that reduce [ATP]i, such as ischemia, de‐repress sGC and amplify responses to NO. Clinical Pharmacology & Therapeutics (2004) 75, P46–P46; doi:

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