Pulmonary edema resulting from high pulmonary venous pressure (PVP) is a major cause of morbidity and mortality in heart failure (HF) patients, but current treatment options demonstrate substantial limitations. Recent evidence from rodent lungs suggests that PVP-induced edema is driven by activation of pulmonary capillary endothelial transient receptor potential vanilloid 4 (TRPV4) channels. To examine the therapeutic potential of this mechanism, we evaluated TRPV4 expression in human congestive HF lungs and developed small-molecule TRPV4 channel blockers for testing in animal models of HF. TRPV4 immunolabeling of human lung sections demonstrated expression of TRPV4 in the pulmonary vasculature that was enhanced in sections from HF patients compared to controls. GSK2193874 was identified as a selective, orally active TRPV4 blocker that inhibits Ca(2+) influx through recombinant TRPV4 channels and native endothelial TRPV4 currents. In isolated rodent and canine lungs, TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP. Furthermore, in both acute and chronic HF models, GSK2193874 pretreatment inhibited the formation of pulmonary edema and enhanced arterial oxygenation. Finally, GSK2193874 treatment resolved pulmonary edema already established by myocardial infarction in mice. These findings identify a crucial role for TRPV4 in the formation of HF-induced pulmonary edema and suggest that TRPV4 blockade is a potential therapeutic strategy for HF patients.

Purpose:To compare atherosclerotic plaque uptake of a first (ferumoxtran-10) and second generation (ferumoxytol) ultrasmall superparamagnetic iron oxide (USPIO) contrast agent with different pharmacokinetic/pharmacodynamic properties. Materials and Methods:New Zealand White rabbits maintained on a high cholesterol/fat diet were subjected to balloon injury to the abdominal aorta. Ferumoxtran-10 or ferumoxytol (500 mol/kg) was administered at 2, 4, and 8 weeks following injury. In vivo magnetic resonance imaging (MRI) was performed immediately prior to, immediately after, and 6 days post-contrast administration. Ex vivo MRI, histologic, and inductively coupled plasma-mass spectrometry (ICP-MS) iron analyses were performed on the excised vessels. Results:The blood pool clearance of ferumoxytol (t 1 ⁄2 Յ 6 hours) was more rapid than that of ferumoxtran-10 (t 1 ⁄2 Յ 48 hours). Decreased in vivo MRI signal intensity in the abdominal aorta was observed at 2, 4, and 8 weeks following injury with ferumoxtran-10, but not with ferumoxytol. Consistent with these observations, ex vivo MRI signal intensity was decreased in the ferumoxtran-10 vessels, and to a lesser degree in the ferumoxytol vs. control vessels (-contrast agent). In contrast, in vitro macrophage phagocytosis of USPIO was four to six fold greater with ferumoxytol than with ferumoxtran-10. Additionally, the absolute iron content correlated with ex vivo MRI signal intensity in all vessels (r ϭ -0.86, P Ͻ 0.0001).

Liver X receptor (LXR) nuclear receptors regulate the expression of genes involved in whole body cholesterol trafficking, including absorption, excretion, catabolism, and cellular efflux, and possess both anti-inflammatory and antidiabetic actions. Accordingly, LXR is considered an appealing drug target for multiple indications. Synthetic LXR agonists demonstrated inhibition of atherosclerosis progression in murine genetic models; however, these and other studies indicated that their major undesired side effect is an increase of plasma and hepatic triglycerides. A significant impediment to extrapolating results with LXR agonists from mouse to humans is the absence in mice of cholesteryl ester transfer protein, a known LXR target gene, and the upregulation in mice but not humans of cholesterol 7 ␣ -hydroxylase. To better predict the human response to LXR agonism, two synthetic LXR agonists were examined in hamsters and cynomolgus monkeys. In contrast to previously published results in mice, neither LXR agonist increased HDL-cholesterol in hamsters, and similar results were obtained in cynomolgus monkeys. Importantly, in both species, LXR agonists increased LDL-cholesterol, an unfavorable effect not apparent from earlier murine studies.These results reveal additional problems associated with current synthetic LXR agonists and emphasize the importance of profiling compounds in preclinical species with a more human-like LXR response and lipoprotein metabolism. The liver X receptors LXR ␣ and LXR ␤ (1) are ligandactivated transcription factors of the nuclear receptor superfamily that control the expression of genes involved in cholesterol homeostasis and fatty acid metabolism (2, 3). LXR ␣ is highly expressed in liver (hence its name) but is also prevalent in adipose tissue, gut, kidney, and macrophages. LXR ␤ is more widely expressed and found in most tissues. Natural ligands for LXRs are oxidized derivatives of cholesterol, such as 24 S -and 25-epoxycholesterol and 24 S -and 22 R -hydroxycholesterol (4-6). LXRs are intracellular cholesterol sensors that upregulate key enzymes and transporters of cholesterol metabolism and transport, such as ABCA1 and ATP binding cassette protein G1 (ABCG1) (7-9), ABCG5 and ABCG8 (10, 11), apolipoprotein E (apoE) in adipocyte and macrophages (12), and cholesteryl ester transfer protein (CETP) (13). In mice but not in primates, hepatic cholesterol 7 ␣ -hydroxylase (cyp7a) is also upregulated by LXR (5,14,15). LXR also affects triacylglycerol metabolism by stimulating lipogenesis and triglyceride synthesis attributable to the upregulation of sterol-regulatory element binding protein 1c (SREBP1c) and the FAS complex (16,17). In addition, LXRs also have direct anti-inflammatory effects by downregulation of several proinflammatory genes in macrophages (18)(19)(20). Based on these data, LXR has been considered an attractive antiatherosclerosis target. Using the potent synthetic LXR agonist GW3965, our group collaborated in a study Abbreviations: ABCG1, ATP binding cassette protei...

Chronic post-myocardial infarction treatment with a selective HIF PHD inhibitor (GSK360A) exerts systemic and local effects by stabilizing HIF-1 alpha signaling and improves long-term ventricular function, remodeling, and vascularity in a model of established ventricular dysfunction. These results suggest that HIF-PHD inhibitors may be suitable for the treatment of post-MI remodeling and heart failure.