15-Hydroxyeicosatetraenoic acid (15-HETE) is produced by the catalytic metabolism of arachidonic acid by the enzyme 15-lipoxygenase. It is produced during hypoxia, and participates in the remodeling of pulmonary artery smooth muscle (PASM). Previous research has revealed that sirtuin 1 (SIRT1) involved in apoptosis in various cells and tissues. Herein, we attempted to determine whether 15-HETE counteracts SIRT1-promoted cell death in murine PASM cells (PASMCs). To verify this theory, we investigated changes in SIRT1 concentration in response to the counteraction of cell death by 15-HETE. We used western blotting and a terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay, and investigated the survival, nuclear morphology, and mitochondrial potential of the cells. Our results revealed that 15-HETE promotes the transcription and translation of SIRT1. Moreover, 15-HETE increases viability and impaired mitochondrial depolarization, and promotes the expression of Bcl-2 and Bcl-xL in PASMCs without serum. The reactions mentioned above were eliminated by SIRT1 inhibitors (EX 527 and SIRT1 inhibitor IV). Our findings suggest that 15-HETE is crucial for the protection of PASMCs against cell death, and the SIRT1 pathway may provide a new strategy for pulmonary artery hypertension therapy.

S-nitrosocaptopril (CapNO) possesses dual capacities of both Captopril and an NO donor with enhanced efficacy and reduced side effects. CapNO crystals are difficult to make due to its unstable S-NO bond. Here, we report a novel stable S-nitrosocaptopril monohydrate (CapNO·H2O) that is stabilized by intermolecular five-membered structure, where one H of H2O forms a hydrogen bond with O- of the stable resonance zwitterion Cap-S+=N-O-, and the O in H2O forms the dipole-dipole interaction with S+ through two unpaired electrons. With the chelation and common ion effect, we synthesized and characterized CapNO·H2O that is stable at 4°C for 180 days and thereafter without significant degradation. Compared to Captopril, CapNO showed direct vasorelaxation and beneficial effect on PAH rats, and could be self-assembled in rat stomach when Captopril and NaNO2 were given separately. This novel CapNO·H2O with low entropy paves an avenue for its clinical trials and commercialization.

Angiotensin II (AngII) stimulates the renal production and release of 20-hydroxyeicosatetraenoic acids (20-HETE), which is a major metabolite of arachidonic acid catalyzed by CYP4 A isoforms. However, the effects of AngII on CYP4 A isoform expression in the kidney and its mechanism remains unclear. To clarify the regulation of CYP4 A isoform expression by AngII, we examined the chronic effects of AngII and AngII type 1 receptor (AT1-R) blockade on CYP4 A isoform expression. Sprague-Dawley rats were infused with vehicle or AngII for 1 week, and the AngII-infused rats were also treated with or without the AT1-R blocker, candesartan. AngII increased CYP4 A isoform protein expression in the renal cortex (CO) and outer medulla (OM) in a dose-dependent manner, and candesartan inhibited the AngII-increased CYP4 A expression in a dose-dependent manner. AngII increased the CYP4 A isoform mRNA expression in the CO and OM, and candesartan inhibited AngII-increased CYP4 A isoform mRNA expression. These results indicated that AngII chronically increased the CYP4 A isoform expression in the rat kidney. The AngII-induced CYP4 A isoform expression was mediated by AT1-R.

Active transportation (AT), or walking or bicycling for transportation, represents one way individuals can achieve recommended physical activity (PA) levels. This study describes AT prevalence and temporal trends, and examines associations between AT levels and measured CVD risk factors (hypertension, hypercholesterolemia, low high-density [HDL] cholesterol, diabetes, and obesity) among U.S. adults. National Health and Nutrition Examination Survey (NHANES) 2007-2016 data (analyzed in 2017) were used to conduct overall trend analyses of reported AT in a typical week [none (0-9 min/week); low (10-149 min/week); or high (≥150 min/week)]. Logistic regression was used to examine associations between AT level and each CVD risk factor from NHANES 2011-2016 (n = 13,943). Covariates included age, sex, race/Hispanic origin, education, income, smoking, survey cycle, non-transportation PA, and urbanization level. U.S. adults who engaged in high AT levels increased from 13.1% in 2007-2008 to 17.9% in 2011-2012, and then decreased to 10.6% in 2015-2016 (p for quadratic trend = 0.004). Over the same period, the quadratic trend for low AT was not significant. During 2011-2016, 14.3% of adults engaged in high AT, 11.4% in low AT, and 74.4% in no AT. High AT levels were associated with decreased odds of each CVD risk factor assessed, compared to no AT. Low AT (versus no AT) was associated with decreased odds of hypertension (aOR = 0.77, 95% CI 0.64, 0.91) and diabetes (aOR = 0.68, 95% CI 0.54, 0.85). AT prevalence among adults has fluctuated from 2007 to 2016. Despite favorable associations between AT and CVD risk factors, most U.S. adults do not engage in any AT.