Myocardial oxidative stress contributes to transgenic β2-adrenoceptor activation-induced cardiomyopathy and heart failure (original) (raw)
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β2-Adrenoceptors, NADPH oxidase, ROS and p38 MAPK: another ‘radical’ road to heart failure?
British Journal of Pharmacology, 2011
Persistent activation of the cardiac b-adrenergic system may contribute to the pathogenesis of congestive heart failure. Both b1-and b2-adrenoceptors are known to mediate these noxious effects, yet the b1-adrenoceptor-PKA axis has received greater attention with less information available on b2-adrenoceptor driven pathways. In the present issue, Xu and colleagues provide new evidence, showing that b2-adrenoceptor over-expression leads to increased reactive oxygen species (ROS) emission, mainly caused by up-regulation of reduced nicotinamide adenine dinucleotide phosphate oxidase (Nox) 2 and 4. Increase in ROS levels is accompanied by p38 mitogen-activated protein kinase activation, fibrosis, apoptosis and cardiac dysfunction. Both Nox inhibition and administration of the antioxidant N-acetyl cysteine prevent these adverse effects. Interestingly, antioxidant treatment also prevents the increase in Nox expression, suggesting that b2-adrenoceptor stimulation triggers a vicious cycle eventually amplified by both Nox isoforms. The possible existence of a circuitry to enhance ROS signalling and detrimental consequences on myocardial remodelling are also discussed, in light of the recent description of intracellular localization of Nox4.
Molecular Pharmacology, 2013
Myocardial connective tissue growth factor (CTGF/CCN2) is induced in heart failure, a condition associated with diminution of β-adrenergic receptor (β-AR) responsiveness. Accordingly, we aimed to investigate whether CTGF could play a mechanistic role in regulation of β-AR responsiveness. Concentration-response curves of isoproterenolstimulated cAMP generation in cardiomyocytes from transgenic mice with cardiacrestricted overexpression of CTGF (Tg-CTGF) or cardiomyocytes pretreated with recombinant human CTGF (rec-hCTGF) revealed marked reduction of both β 1-AR and β 2-AR responsiveness. Consistently, ventricular muscle strips from Tg-CTGF mice stimulated with isoproterenol displayed attenuation of maximal inotropic responses. However, no differences of maximal inotropic responses of myocardial fibres from Tg-CTGF mice and non-transgenic littermates (NLC) were discerned when stimulated with supramaximal concentrations of dibutyryl-cAMP, indicating preserved downstream responsiveness to cAMP. Congruent with a mechanism of desensitization of β-ARs, mRNA and protein levels of GRK5 were found isoform-selective upregulated in both cardiomyocytes from Tg-CTGF mice and cardiomyocytes exposed to rec-hCTGF. Corroborating a mechanism of GRK5 in CTGF-mediated control of β-AR sensitivity, CHO cells pretreated with rec-hCTGF displayed increased agonist-and biased ligandstimulated β-arrestin-binding to β-ARs. Despite increased sensitivity of cardiomyocytes from GRK5-knockout mice (GRK5-KO) to β-adrenergic agonist, pretreatment of GRK5-KO cardiomyocytes with rec-hCTGF, as opposed to cardiomyocytes from wild type mice, did not alter β-AR responsiveness. Finally, Tg-CTGF mice subjected to chronic (14 days) exposure to isoproterenol, revealed blunted myocardial hypertrophy and This article has not been copyedited and formatted. The final version may differ from this version.
Inflammation, 2008
We investigated whether or not p38 mitogen-activated protein kinase inhibition ameliorates angiotensin II-induced target organ damage. We used double transgenic rats harboring both human renin and angiotensinogen genes (dTGRs). dTGR, with or without p38 inhibitor (BIRB796; 30 mg/kg per day in the diet), and nontransgenic Sprague-Dawley rats were studied in 2 protocols. In protocol 1 (week 7), systolic blood pressure of untreated dTGRs was 204Ϯ4 mm Hg, but partially reduced after BIRB796 treatment (166Ϯ7 mm Hg), whereas Sprague-Dawley rats were normotensive. The cardiac hypertrophy index was unchanged in untreated and BIRB796-treated dTGRs. The -myosin heavy chain expression of BIRB796-treated hearts was significantly lower in BIRB796 compared with dTGRs, indicating a delayed switch to the fetal isoform. BIRB796 treatment significantly reduced cardiac fibrosis, connective tissue growth factor, tumor necrosis factor-␣, interleukin-6, and macrophage infiltration. Albuminuria was not reduced in BIRB796-treated dTGRs. Tubular and glomerular damage with tumor necrosis factor-␣ expression was unaltered, although serum creatinine and cystatin C were normalized. Renal macrophage infiltration, fibrosis, and vessel damage were reduced. In protocol 2 (week 8), we focused on mortality and arrhythmogenic electrical remodeling. Mortality of untreated dTGRs was 100% but was reduced to 10% in the BIRB796 group. Cardiac magnetic field mapping showed prolongation of depolarization and repolarization in untreated dTGRs compared with Sprague-Dawley rats with a partial reduction by BIRB796. Programmed electrical stimulation elicited ventricular tachycardias in 81% of untreated dTGRs but only in 48% of BIRB796-treated dTGRs. In conclusion, BIRB796 improved survival, target organ damage, and arrhythmogenic potential in angiotensin II-induced target organ damage. (Hypertension. 2007;49:1-9.) Key Words: angiotensin II Ⅲ p38 Ⅲ electrical remodeling Ⅲ cardiac and renal damage
Role of Oxidative Stress in Cardiac Hypertrophy and Remodeling
Hypertension, 2006
C ardiac adaptation in response to intrinsic or external stress involves a complex process of chamber remodeling and myocyte molecular modifications. A fundamental response to increased biomechanical stress is cardiomyocyte and chamber hypertrophy. Although this may provide initial salutary compensation to the stress, sustained hypertrophic stimulation becomes maladaptive, worsening morbidity and mortality risks because of congestive heart failure and sudden death. 1 Growing evidence highlights oxidative and nitrosative stresses as important mechanisms for this maladaptation. Oxidative stress occurs when excess reactive oxygen species (ROS) are generated that cannot be adequately countered by intrinsic antioxidant systems. Superoxide anion (O 2 Ϫ ) can further combine with NO, forming reactive compounds such as peroxynitrite, generating nitroso-redox imbalance. 4 ROS generation is a normal component of oxidative phosphorylation and plays a role in normal redox control of physiological signaling pathways. However, excessive ROS generation triggers cell dysfunction, lipid peroxidation, and DNA mutagenesis and can lead to irreversible cell damage or death. In this review, we discuss recent experimental evidence for the role of oxidant stress on cardiac remodeling, focusing on pressureoverload-induced hypertrophy and dilation.
AJP: Heart and Circulatory Physiology, 2006
p38 MAPK is activated during heart diseases that might associate with myocardial damage and deterioration of cardiac function. In a rat model of myocardial injury, we have investigated cardioprotective effects of the inhibition of p38 MAPK using a novel, orally available p38α MAPK inhibitor. Rats were treated with Nω-nitro-l-arginine methyl ester (l-NAME, 40 mg·kg−1·day−1) in drinking water plus 1% salt for 14 days and ANG II (0.5 mg·kg−1·day−1) for 3 days. A selective p38α MAPK inhibitor, SD-282 (60 mg/kg), was administrated orally, twice a day for 4 days, starting 1 day before ANG II administration. The cardioprotective effects of p38α MAPK inhibition were evaluated by improvement of cardiac function, reduction of inflammatory cell infiltration, and cardiomyocyte apoptosis. SD-282 significantly improved cardiac function indicated by increasing stroke volume, cardiac output, ejection fraction, and stroke work and significantly decreasing arterial elastance. SD-282 also significantl...