NADPH oxidase inhibition ameliorates cardiac dysfunction in rabbits with heart failure

Abstract

Increased NADPH oxidase activity is found in both experimental and clinical HF. Here, we investigated the effects and mechanisms of NADPH oxidase inhibition on cardiac function in rabbits with HF. HF was induced by combined volume and pressure overload. Rabbits with HF or sham operation were randomized to orally receive apocynin, an inhibitor of NADPH oxidase (15 mg per day) or placebo for 8 weeks. Echocardiography was performed to examine the cardiac function and structure of the rabbits. Cardiac fibrosis was evaluated by masson's trichrome staining. The transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) expression were measured by real-time PCR. The expression of SERCA2a and phospholamban (PLB) was detected by reverse transcription-polymerase chain reaction and Western Blot. SERCA2a activity was evaluated by measuring the Pi liberated from ATP hydrolysis. Rabbits with HF exhibited cardiac dysfunction and fibrosis. These changes were associated with significant increases in myocardial NADPH oxidase activity and oxidative stress. Compared with sham-operated rabbits, the TGF-β, CTGF, MMP-2, and MMP-9 mRNA expression significantly increased, the expression of SERCA2a and PLB dramatically decreased, and the SERCA2a activity was lower in HF rabbits. Apocynin reduced NADPH oxidase activity and oxidative stress, decreased TGF-β, CTGF, MMP-2, and MMP-9 expression, attenuated cardiac fibrosis, increased SERCA2a and PLB expression, restored SERCA2a activity, and thereby ameliorated cardiac dysfunction. Thus, chronic NADPH oxidase inhibition ameliorated cardiac dysfunction by decreasing cardiac fibrosis and preserving SERCA2a expression and activity.

CYP2J2-Derived Epoxyeicosatrienoic Acids Suppress Endoplasmic Reticulum Stress in Heart Failure

“…A growing body of evidence suggests that ROS is increased and plays an important role in heart failure (Seddon et al, 2007;Liu et al, 2010), and ROS could depress the activity of SERCA2a (Kaneko et al, 1989a,b). Indeed, we observed 2+ levels and overexpression of p-CaM-KII in H9C2 cells exposed to ISO or AngII, respectively (n = 3 for each experiment).…”

“…A growing body of evidence suggests that ROS is increased and plays an important role in heart failure (Seddon et al, 2007;Liu et al, 2010), and that ROS depresses the activity of SERCA2a (Kaneko et al, 1989a,b). In addition, CYP2J2 overexpression has been shown to suppress ROS levels (Liu et al, 2011).…”

“…Restoration of SERCA2a expression by gene transfer effectively improves cardiac function in animal models (Adachi et al, 2004), as well as in patients with heart failure (Jessup et al, 2011). Previous studies demonstrated that the activity of SERCA2a is decreased by ROS, which is increased in heart failure (Kaneko et al, 1989a,b;Liu et al, 2010). Indeed, several thiol residues in SERCA2a are potential targets for oxidation (Adachi et al, 2004;Gutiérrez-Martin et al, 2004;Cohen and Adachi, 2006;Dremina et al, 2007).…”

NADPH Oxidases in Heart Failure: Poachers or Gamekeepers?

“…It was reported that TNF-a-induced induction of MMPs in cardiomyocytes involves Nox and PI3Kc (11). Noxmediated MMP activation has also been shown in rabbit hearts in response to combined volume and pressure overload (135), and in age-related cardiac fibrosis in rats (199). Aldosteroneinduced in vivo myocardial fibrosis in mice involves the Nox2-dependent activation of NF-jB; upregulation of the profibrotic cytokine connective tissue growth factor; increased expression of procollagen-1, 3, and fibronectin; and increased MMP2 activation (100).…”

Abnormal Ca2+Cycling in Failing Ventricular Myocytes: Role of NOS1-Mediated Nitroso-Redox Balance

“…Furthermore, under these oxidative conditions, the mitochondria will also produce large amounts of H 2 O 2 (9,150). NOX activity is also increased with HF (75,104,107,128 -, superoxide anion; XO, xanthine oxidase. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars levels, post-translational modification and membrane translocation of subunits (e.g., p47…”