ABSTRACT
BACKGROUND: Oxidative stress is involved in progression of left ventricular hypertrophy and heart failure. Since NADPH oxidases are a major source of reactive oxygen species in the heart, we studied left ventricular remodeling after myocardial infarction in mice with targeted deletion of the NADPH oxidase subunit gp91(phox). METHODS AND RESULTS: gp91(phox) knockout (KO) and wild-type (WT) animals underwent coronary artery ligation. Mortality was significant higher in the gp91(phox) KO mice. However, transthoracic echocardiography performed at days 1, 7, and 56 at mid-papillary levels revealed that progression of left ventricular remodeling was not influenced by the genotype. Moreover, systemic oxidative stress was not reduced in gp91(phox) KO mice as indicated by a significant increase in lipid peroxides potentially mediated by an increase of the NADPH subunit nox-1 in gp91(phox) KO mice. CONCLUSION: Targeted deletion of the NADPH subunit gp91(phox) does not affect left ventricular remodeling following myocardial infarction and does not decrease the production of oxidative stress. However, the final role of the different NADPH subunits in the heart under pathophysiologic conditions remains to be determined.
Subject(s)
Membrane Glycoproteins/genetics , Myocardial Infarction/physiopathology , NADPH Oxidases/genetics , Ventricular Remodeling/genetics , Animals , Echocardiography , Gene Deletion , Mice , Mice, Knockout , NADPH Oxidase 2 , Oxidative Stress/physiologyABSTRACT
BACKGROUND: Men and women are differently affected by coronary artery disease, suggesting an important role of sex steroids. Moreover, testosterone (T) treatment is increasingly used in elderly males. Therefore, we examined effects of chronic anabolic T administration on left ventricular (LV) remodeling after myocardial infarction (MI). METHODS: Adult male rats were treated with intramuscular placebo, testosterone undecanoate (T), or were orchiectomized. After 2 weeks, animals underwent sham-operation (sham) or left coronary artery ligation. Left ventricular remodeling and function was assessed by serial magnetic resonance imaging (MRI) at weeks 2 and 8 and hemodynamic investigation at week 8. RESULTS: In sham operated animals T administration increased serum T levels and led to cardiac hypertrophy, but not to an upregulation of ANP mRNA. The alpha/beta-MHC ratio was significantly higher after T treatment due to an increase in alpha-MHC. As a potential mechanism for this "physiologic" form of hypertrophy, IGF-1 mRNA expression was significantly increased in T treated animals. After coronary artery ligation, infarct size and mortality were similar among the groups. Left ventricular hypertrophy was enhanced by T treatment. However, in vivo LV end-diastolic pressure and wall stress were decreased by T, whereas other hemodynamic parameters (mean arterial pressure, cardiac output, etc.) remained unchanged. CONCLUSION: Chronic anabolic T treatment led to a specific "physiologic" pattern of myocardial hypertrophy with a significant increase in LV weight, but without differences in ANP and with an upregulation in alpha/beta-MHC, possibly mediated by IGF-1. Testosterone treatment had no detrimental effects following MI. Reduced wall stress and LVEDP may even improve long-term outcome.
