Many advances have been made in the diagnosis and management of heart failure (HF) in recent years. Cardiac biomarkers are an essential tool for clinicians: point of care B-Type Natriuretic Peptide (BNP) and its N-terminal counterpart (NT-proBNP) levels help distinguish cardiac from non-cardiac causes of dyspnea and are also useful in the prognosis and monitoring of the efficacy of therapy. One of the major limitations of HF biomarkers is in obese patients where the relationship between BNP and NT-proBNP levels and myocardial stiffness is complex. Recent data suggest an inverse relationship between BNP and NT-proBNP levels and body mass index. Given the ever-increasing prevalence of obesity world-wide, it is important to understand the benefits and limitations of HF biomarkers in this population. This review will explore the biology, physiology, and pathophysiology of these peptides and the cardiac endocrine paradox in HF. We also examine the clinical evidence, mechanisms, and plausible biological explanations for the discord between BNP levels and HF in obese patients.

Objective-We previously showed that NAD(P)H oxidase deficiency significantly reduces atherosclerosis in apoE Ϫ/Ϫ mice. The present study was designed to determine the relative contribution of monocyte/macrophage versus vascular wall cell NAD(P)H oxidase to atherogenesis in this model. Methods and Results-Cell-specific NAD(P)H oxidase inhibition was achieved via allogenic, sex-mismatched bone marrow transplantation. Aortic atherosclerosis and superoxide production in apoE Ϫ/Ϫ mice (Control) with functional NAD(P)H oxidase in both monocytes/macrophages and vascular wall cells was compared with that in apoE Ϫ/Ϫ mice with nonfunctional monocyte/macrophage NAD(P)H oxidase (BMO) or nonfunctional vessel wall NAD(P)H oxidase (VWO). A significant decrease in superoxide production and atherosclerotic lesions was observed in BMO and VWO mice compared with control mice. Interestingly, BMO mice had significantly lower plasma oxidized LDL levels compared with control and VWO mice, whereas aortic sections of VWO mice showed decreased expression of cellular adhesion molecules compared with control and BMO mice. NAD(P)H oxidase deficiency also attenuated neointimal hyperplasia and mitogenic protein activation in apoE Ϫ/Ϫ mice after arterial injury. Conclusions-We conclude that (1) both monocyte/macrophages and vessel wall cells play critical roles in atherogenesis;(2) decrease in atherosclerosis results from attenuated superoxide generation in monocyte/macrophages or vessel wall cells; and (3) Key Words: Adhesion molecules Ⅲ signal transduction Ⅲ oxidized lipids Ⅲ reactive oxygen species Ⅲ thrombin R eactive oxygen species (ROS) derived from NAD(P)H oxidase have been strongly associated with experimental hypertension, 1 cardiac hypertrophy, 2 thrombosis, 3 restenosis, and atherosclerosis. 4 In humans, higher expression of NAD(P)H oxidase subunit proteins is associated with increased superoxide (O 2 ⅐Ϫ ) production and severity of atherosclerosis. 5 NAD(P)H oxidase is also an important source of increased O 2 ⅐Ϫ production in human diabetes mellitus, a risk factor for atherosclerosis. 6 All vascular wall cells-endothelial cells, smooth muscle cells (SMCs), and fibroblasts-as well as monocytes/macrophages contain NAD(P)H oxidases which are activated under pathophysiological conditions. The resultant ROS induce redox-sensitive signaling pathways that contribute to atherogenesis. 7 The phagocytic NAD(P)H oxidase contains the membranebound subunits gp91phox (Nox2) and p22phox, the catalytic site of the oxidase and the cytosolic components p47phox, p67phox, and G-protein Rac1 or Rac2. 8 Vascular NAD(P)H oxidases are similar in structure to phagocytic NAD(P)H oxidase, but have a distinct molecular composition. Endothelial cells and adventitial fibroblasts possess all the components of the phagocytic oxidase, whereas SMCs predominantly express homologues of gp91phox, Nox1 and Nox4. Mouse SMCs also express a p67phox homologue, Noxa1. 9 The activation of vascular NAD(P)H oxidases is constitutive as well as inducible in a manner similar ...

Background-Despite a concerted effort by many laboratories, the critical subunits that participate in vascular smooth muscle cell (VSMC) NADPH oxidase function have yet to be elucidated. Given the potential therapeutic importance of cell-specific inhibition of NADPH oxidase, we investigated the role of Nox activator 1 (NoxA1), a homolog of p67phox, in VSMC NADPH oxidase function and atherosclerosis. Methods and Results-The presence of NoxA1 in mouse aortic VSMCs was confirmed by reverse-transcription polymerase chain reaction and sequencing. NoxA1/p47phox interaction after thrombin treatment was observed by immunoprecipitation/ Western analysis of lysates from p47phox Ϫ/Ϫ VSMCs transfected with adenoviral HA-NoxA1 and Myc-p47phox. Infection with adenoviral NoxA1 significantly enhanced thrombin-induced reactive oxygen species generation in wild-type but not in p47phox Ϫ/Ϫ and Nox1 Ϫ/Ϫ VSMCs. Thrombin-induced reactive oxygen species production and VSMC proliferation were significantly reduced after downregulation of NoxA1 with shRNA. Infection with NoxA1 shRNA but not scrambled shRNA significantly decreased thrombin-induced activation of the redox-sensitive protein kinases (Janus kinase 2, Akt, and p38 mitogen-activated protein kinase) in VSMCs. Adenovirus-mediated overexpression of NoxA1 in guidewire-injured mouse carotid arteries significantly increased superoxide production in medial VSMCs and enhanced neointimal hyperplasia. NoxA1 expression was significantly increased in aortas and atherosclerotic lesions of ApoE Ϫ/Ϫ mice compared with age-matched wild-type mice. Furthermore, in contrast to p67phox, immunoreactive NoxA1 is present in intimal and medial SMCs of human early carotid atherosclerotic lesions. Conclusions-NoxA1 is the functional homolog of p67phox in VSMCs that regulates redox signaling and VSMC phenotype. These findings support the potential for modulation of NoxA1 expression as a viable approach for the treatment of vascular diseases. (Circulation. 2010;121:549-559.)