We rescued the embryonic lethality of global PPARγ knockout by breeding Mox2-Cre (MORE) mice with floxed PPARγ mice to inactivate PPARγ in the embryo but not in trophoblasts and created a generalized PPARγ knockout mouse model, MORE-PPARγ knockout (MORE-PGKO) mice. PPARγ inactivation caused severe lipodystrophy and insulin resistance; surprisingly, it also caused hypotension. Paradoxically, PPARγ agonists had the same effect. We showed that another mouse model of lipodystrophy was hypertensive, ruling out the lipodystrophy as a cause. Further, high salt loading did not correct the hypotension in MORE-PGKO mice. In vitro studies showed that the vasculature from MORE-PGKO mice was more sensitive to endothelial-dependent relaxation caused by muscarinic stimulation, but was not associated with changes in eNOS expression or phosphorylation. In addition, vascular smooth muscle had impaired contraction in response to α-adrenergic agents. The renin-angiotensin-aldosterone system was mildly activated, consistent with increased vascular capacitance or decreased volume. These effects are likely mechanisms contributing to the hypotension. Our results demonstrated that PPARγ is required to maintain normal adiposity and insulin sensitivity in adult mice. Surprisingly, genetic loss of PPARγ function, like activation by agonists, lowered blood pressure, likely through a mechanism involving increased vascular relaxation.

Background-Aldosterone has been implicated in the effects of angiotensin II in the vasculature. We hypothesized that there is local expression of the mineralocorticoid receptor (MR) in the vasculature and that the use of a selective aldosterone receptor antagonist (SARA) improves endothelial function in early atherosclerosis. Methods and Results-New Zealand rabbits were placed on normal chow or 1% cholesterol diets, randomized to placebo or SARA (eplerenone, 50 mg/kg twice daily), and killed at the end of 6 weeks for various studies. In the hyperlipidemic (HL) chow group, there was a 2.3-fold increase in superoxide (O 2 ⅐Ϫ ) generation. SARA normalized O 2 ⅐Ϫ generation in intact aortas and reduced NADH and NADPH oxidase activity to basal levels (0.31Ϯ0.04 and 0.27Ϯ0.02 in HL versus 0.16Ϯ0.05 and 0.07Ϯ0.02 in HL-SARA, respectively; PϽ0.01 by ANOVA). This was associated with improvements in peak relaxations to the endothelial-dependent agonist acetylcholine (82Ϯ6% in HL-SARA versus 61Ϯ4 in HL; PϽ0.01 by ANOVA; ED 50 6.8ϫ10Ϫ8 mol/L in HL-SARA and 1.2ϫ10 Ϫ7 mol/L in HL; PϭNS) to near-normal levels. Vessels from the HL group demonstrated hyperreactivity to angiotensin II that could not be corrected with SARA. Plasma aldosterone levels by radioimmunoassay demonstrated a 4-to 5-fold increase in response to SARA but no differences with lipid feeding. Real-time reverse transcriptase-polymerase chain reaction studies revealed expression of MR in the aorta of HL rabbits and those of controls. Conclusions-MR antagonism improves endothelial function and reduces O 2⅐Ϫ generation in diet-induced atherosclerosis. Targeting aldosterone by blocking its receptor has potential antiatherosclerotic effects.

Physicians who are insufficiently prepared to make choices on antibiotic selection may use antibiotics inappropriately. We surveyed medical students' perceptions and attitudes about their training on antimicrobial use to identify gaps in medical education. Medical students at an urban medical school in the northeast were e-mailed a link to an online survey. The survey was online for 1 week, after which time the survey responses were downloaded and analyzed. Thirty percent of medical students responded to the survey (n  =  304). The majority of third- and fourth-year medical students believe that antibiotics are overused in the hospital and in outpatient areas. Over three quarters of the students would like more education on antibiotic selection, and 83% wanted this education to be during the third year of medical school. The resources they used the most for antibiotic selection included other physicians and handheld programs such as Epocrates, but no clear resource emerged as the dominant preference. Medical students recognized the importance of judicious antibiotic use and would like greater instruction on how to choose antibiotics appropriately. Medical school curricula should be expanded in the third year of medical school to provide students with additional training timed with their clinical rotations.

Background-Iron overload has been implicated in the pathogenesis of ischemic cardiovascular events. However, the effects of iron excess on vascular function and the thrombotic response to vascular injury are not well understood. Methods and Results-We examined the effects of chronic iron dextran administration (15 mg over 6 weeks) on thrombosis, systemic and vascular oxidative stress, and endothelium-dependent vascular reactivity in mice. Thrombus generation after photochemical carotid artery injury was accelerated in iron-loaded mice (mean time to occlusive thrombosis, 20.4Ϯ8.5 minutes; nϭ10) compared with control mice (54.5Ϯ35.5 minutes, nϭ10, Pϭ0.009). Iron loading had no effect on plasma clotting, vessel wall tissue factor activity, or ADP-induced platelet aggregation. Acute administration of DL-cysteine, a reactive oxygen species scavenger, completely abrogated the effects of iron loading on thrombus formation, suggesting that iron accelerated thrombosis through a pro-oxidant mechanism. Iron loading enhanced both systemic and vascular reactive oxygen species production. Endothelium-dependent vasorelaxation was impaired in iron-loaded mice, indicating reduced NO bioavailability. Conclusions-Moderate iron loading markedly accelerates thrombus formation after arterial injury, increases vascular oxidative stress, and impairs vasoreactivity. Iron-induced vascular dysfunction may contribute to the increased incidence of ischemic cardiovascular events that have been associated with chronic iron overload.