The absence of Bmal1, a core clock gene, results in a loss of circadian rhythms, an acceleration of aging, and a shortened life span in mice. To address the importance of circadian rhythms in the aging process, we generated conditional Bmal1 knockout mice that lacked the BMAL1 protein during adult life and found that wild-type circadian variations in wheel-running activity, heart rate, and blood pressure were abolished. Ocular abnormalities and brain astrogliosis were conserved irrespective of the timing of Bmal1 deletion. However, life span, fertility, body weight, blood glucose levels, and age-dependent arthropathy, which are altered in standard Bmal1 knockout mice, remained unaltered, whereas atherosclerosis and hair growth improved, in the conditional adult-life Bmal1 knockout mice, despite abolition of clock function. Hepatic RNA-Seq revealed that expression of oscillatory genes was dampened in the adult-life Bmal1 knockout mice, whereas overall gene expression was largely unchanged. Thus, many phenotypes in conventional Bmal1 knockout mice, hitherto attributed to disruption of circadian rhythms, reflect the loss of properties of BMAL1 that are independent of its role in the clock. These findings prompt reevaluation of the systemic consequences of disruption of the molecular clock.

Persons with low socioeconomic status and nonwhite persons in the United States have high rates of cardiovascular disease. The use of combination pills (also called “polypills”) containing low doses of medications with proven benefits for the prevention of cardiovascular disease may be beneficial in such persons. However, few data are available regarding the use of polypill therapy in underserved communities in the United States, in which adherence to guideline-based care is generally low.

Background— Microsomal prostaglandin (PG) E ₂ synthase-1 (mPGES-1) catalyzes isomerization of the cyclooxygenase product PGH ₂ into PGE ₂ . Deletion of mPGES-1 modulates experimentally evoked pain and inflammation and retards atherogenesis. The role of mPGES-1 in abdominal aortic aneurysm is unknown. Methods and Results— The impact of mPGES-1 deletion on formation of angiotensin II–induced abdominal aortic aneurysm was studied in mice lacking low-density lipoprotein receptor (LDLR ^−/− ). Male mice deficient in both mPGES-1 and LDLR (mPGES-1 ^−/− LDLR ^−/− ) and littermate LDLR ^−/− mice were initiated on a high-fat diet at 6 months of age, followed 1 week later by continuous infusion of angiotensin II (1 μg/kg per minute) for an additional 4 weeks. Angiotensin II infusion upregulated aortic expression of cyclooxygenase-2 and mPGES-1, increased aortic macrophage recruitment and vascular nitrotyrosine staining (which reflects local oxidative stress), and augmented urinary excretion of the isoprostane 8,12- iso -iPF _2α -VI (which reflects lipid peroxidation in vivo) and the major metabolite of PGE ₂ (PGE-M). Deletion of mPGES-1 decreased both the incidence (87.5% versus 27.3%; P =0.02) and the severity of abdominal aortic aneurysm and depressed the aortic and systemic indices of oxidative stress. Deletion of mPGES-1 also depressed urinary PGE-M, whereas it augmented excretion of PGD ₂ and PGI ₂ metabolites, reflecting rediversion of the accumulated PGH ₂ substrate in the double knockouts. Conclusions— Deletion of mPGES-1 protects against abdominal aortic aneurysm formation induced by angiotensin II in hyperlipidemic mice, coincident with a reduction in oxidative stress. The potential efficacy of selective inhibition of mPGES-1 in preventing or retarding aneurysm formation warrants further investigation.

Suppression of prostacyclin (PGI ₂ ) biosynthesis may explain the increased incidence of myocardial infarction and stroke which has been observed in placebo controlled trials of cyclooxygenase (COX)-2 inhibitors. Herein, we examine if COX-2–derived PGI ₂ might condition the response of the vasculature to sustained physiologic stress in experimental models that retain endothelial integrity. Deletion of the PGI ₂ receptor (IP) or suppression of PGI ₂ with the selective COX-2 inhibitor, nimesulide, both augment intimal hyperplasia while preserving luminal geometry in mouse models of transplant arteriosclerosis or flow-induced vascular remodeling. Moreover, nimesulide or IP deletion augments the reduction in blood flow caused by common carotid artery ligation in wild-type mice. Generation of both thromboxane (Tx)A ₂ and the isoprostane, 8, 12 – iso iPF _2α -VI, are increased in the setting of flow reduction and the latter increases further on administration of nimesulide. Deletion of the TxA ₂ receptor (TP) reduces the hyperplastic response to nimesulide and carotid ligation, despite further augmentation of TP ligand production. Suppression of COX-2–derived PGI ₂ or deletion of IP profoundly influences the architectural response of the vasculature to hemodynamic stress. Mechanism based vascular remodeling may interact with a predisposition to hypertension and atherosclerosis in contributing to the gradual transformation of cardiovascular risk during extended periods of treatment with selective inhibitors of COX-2.

Prostaglandin D₂ (PGD₂) is a cyclooxygenase (COX) product of arachidonic acid that activates D prostanoid receptors to modulate vascular, platelet, and leukocyte function in vitro. However, little is known about its enzymatic origin or its formation in vivo in cardiovascular or inflammatory disease. 11,15-Dioxo-9α-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid (tetranor PGDM) was identified by mass spectrometry as a metabolite of infused PGD₂ that is detectable in mouse and human urine. Using liquid chromatography-tandem mass spectrometry, tetranor PGDM was much more abundant than the PGD₂ metabolites, 11β-PGF_2α and 2,3-dinor-11β-PGF_2α, in human urine and was the only endogenous metabolite detectable in mouse urine. Infusion of PGD₂ dose dependently increased urinary tetranor PGDM > 2,3-dinor-11β-PGF_2α > 11β-PGF_2α in mice. Deletion of either lipocalin-type or hemopoietic PGD synthase enzymes decreased urinary tetranor PGDM. Deletion or knockdown of COX-1, but not deletion of COX-2, decreased urinary tetranor PGDM in mice. Correspondingly, both PGDM and 2,3-dinor-11β-PGF_2α were suppressed by inhibition of COX-1 and COX-2, but not by selective inhibition of COX-2 in humans. PGD₂ has been implicated in both the development and resolution of inflammation. Administration of bacterial lipopolysaccharide coordinately elevated tetranor PGDM and 2,3-dinor-11β-PGF_2α in volunteers, coincident with a pyrexial and systemic inflammatory response, but both metabolites fell during the resolution phase. Niacin increased tetranor PGDM and 2,3-dinor-11β-PGF_2α in humans coincident with facial flushing. Tetranor PGDM is an abundant metabolite in urine that reflects modulated biosynthesis of PGD₂ in humans and mice.