No abstract

Vascular oxidative injury accompanies many common conditions associated with hypertension. In the present study, we employed mouse models with excessive vascular production of ROS (tg(sm/p22phox) mice, which overexpress the NADPH oxidase subunit p22(phox) in smooth muscle, and mice with vascular-specific deletion of extracellular SOD) and have shown that these animals develop vascular collagen deposition, aortic stiffening, renal dysfunction, and hypertension with age. T cells from tg(sm/p22phox) mice produced high levels of IL-17A and IFN-γ. Crossing tg(sm/p22phox) mice with lymphocyte-deficient Rag1(-/-) mice eliminated vascular inflammation, aortic stiffening, renal dysfunction, and hypertension; however, adoptive transfer of T cells restored these processes. Isoketal-protein adducts, which are immunogenic, were increased in aortas, DCs, and macrophages of tg(sm/p22phox) mice. Autologous pulsing with tg(sm/p22phox) aortic homogenates promoted DCs of tg(sm/p22phox) mice to stimulate T cell proliferation and production of IFN-γ, IL-17A, and TNF-α. Treatment with the superoxide scavenger tempol or the isoketal scavenger 2-hydroxybenzylamine (2-HOBA) normalized blood pressure; prevented vascular inflammation, aortic stiffening, and hypertension; and prevented DC and T cell activation. Moreover, in human aortas, the aortic content of isoketal adducts correlated with fibrosis and inflammation severity. Together, these results define a pathway linking vascular oxidant stress to immune activation and aortic stiffening and provide insight into the systemic inflammation encountered in common vascular diseases.

Background Cardiomyocyte hypertrophy is a critical precursor to the development of heart failure. Methods to phenotype cellular hypertrophy non-invasively are limited. The goal was to validate a CMR-based approach for the combined assessment of extracellular matrix expansion and cardiomyocyte hypertrophy. Methods and Results Two murine models of a) hypertension (N=18, with N=15 controls) induced by L-NG-Nitroarginine Methyl Ester (L-NAME) and b) pressure-overload (N=11) from transaortic constriction (TAC), were imaged by CMR at baseline and 7-weeks after L-NAME treatment, or up to 7 weeks following TAC. T1 relaxation times were measured before and after gadolinium contrast. The intracellular lifetime of water (τic), a cell size dependent parameter, and extracellular volume fraction (ECV), a marker of interstitial fibrosis, were determined with a model for transcytolemmal water exchange. Cardiomyocyte diameter and length were measured on FITC-wheat germ agglutinin stained sections. τic correlated strongly with histologic cardiomyocyte volume-to-surface ratio (r=0.78, P<0.001) and cell volume (r=0.75; P<0.001). Histological cardiomyocyte diameters and cell volume were higher in mice treated with L-NAME compared to controls (P<0.001). In the TAC model, CMR and histology showed an cell hypertrophy at two weeks post TAC, without significant fibrosis at this early time point. Mice exposed to TAC demonstrated a significant, longitudinal, and parallel increase in histological cell volume, volume-to-surface ratio, and τic,between 2 and 7 weeks after TAC. Conclusion The intracellular lifetime (τic) measured by contrast-enhanced CMR provides a non-invasive measure of cardiomyocyte hypertrophy. ECV and τic can track myocardial tissue remodeling from pressure overload.

The negative impact of smoking on implant outcomes may be related to more than one molecule present in the cigarette smoke and nicotine seems to partially contribute, especially in the cancellous bone.

Background-The myocardial extracellular volume fraction (MECVF) has been used to detect diffuse fibrosis. Estimation of MECVF relies on quantification of the T1 relaxation time after contrast enhancement, which can be sensitive to equilibrium transcytolemmal water-exchange. We hypothesized that MECVF, quantified with a parsimonious 2-space water-exchange model, correlates positively with the connective tissue volume fraction in a rodent model of hypertensive heart disease, whereas the widely used analysis based on assuming fast transcytolemmal water-exchange could result in a significant underestimate of MECVF. Methods and Results-Nω-nitro-L-arginine-methyl-ester (L-NAME) or placebo was administered to 22 and 15 wild-type mice, respectively. MECVF was measured at baseline and 7-week follow-up by pre-and postcontrast T1 cardiac magnetic resonance imaging at 4.7 T, using a 2-space water-exchange model.