Levels of the soluble LDL receptor-relative LR11 decrease in overweight individuals with type 2 diabetes upon diet-induced weight loss

__Background and aims__ Cardiovascular disease (CVD) is a major complication in patients with type 2 diabetes (T2D), especially in those with obesity. Plasma soluble low density lipoprotein receptor-relative with 11 ligand-binding repeats (sLR11) plays a role in the development of atherosclerosis and has been linked to the metabolism of triglyceride-rich lipoproteins, adiposity, and vascular complications in T2D. We aimed to determine the effect of diet-induced weight loss on plasma sLR11 levels in overweight and obese individuals with T2D. __Methods__ Plasma sLR11 levels were determined in 64 individuals with T2D and BMI >27 kg/m2 before and after a 20-week weight loss diet. As a reference, sLR11 levels were also determined in 64 healthy, non-obese controls, matched as a group for age and sex. __Results__ Median plasma sLR11 levels of the T2D study-group at baseline (15.4 ng/mL (IQR 12.9–19.5)) were higher than in controls (10.2 (IQR: 8.7–12.2) ng/mL; p = 0.001). The diet resulted in a weight loss of 9.7 ± 5.2% (p = 0.001) and improved CVD risk factors. sLR11 levels were reduced to 13.3 ng/mL (IQR 11.0–17.1; p = 0.001). Changes in sLR11 levels positively associated with changes in non-HDL cholesterol (B = 1.54, R2 = 0.17, p = 0.001) and HbA1c (B = 0.07, R2 = 0.11, p = 0.007), but not with weight loss (B = 0.04, R2 = 0.05, p = 0.076). The changes in non-HDL cholesterol and HbA1c together explained 24% of the variance of sLR11 reduction (p = 0.001). __Conclusions__ Weight loss dieting in overweight and obese individuals with T2D resulted in a reduction in plasma sLR11 levels that was associated with improvements in lipid-profile and glycemic state

Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice

Disruption of leptin signaling in the heart may contribute to obesity-related cardiac disease, as leptin deficient (ob/ob) mice display cardiac hypertrophy, increased cardiac apoptosis and reduced survival. Since leptin maintains a tonic level of neuronal nitric oxide synthase (NOS1) expression in the brain, we hypothesized that leptin deficiency would decrease 1 cardiac expression, in turn activating xanthine oxidoreductase (XOR) and creating nitroso-redox imbalance. We studied 2- to 6-month-old ob/ob (n = 26) and C57B1/6 controls (n = 27). Cardiac NOS1 protein abundance (P < 0.01) and mRNA expression (P = 0.03) were reduced in ob/ob (n = 10 and 6, respectively), while NOS3 protein abundance and mRNA expression were unaltered. Importantly, cardiac NOS1 protein abundance was restored towards normal in ob/ob mice after leptin treatment (n = 3; P < 0.05 vs leptin untreated ob/ob mice). NO metabolite (nitrite and nitrate) production within the myocardium was also reduced in ob/ob mice (n = 5; P = 0.02). Furthermore, oxidative stress was increased in ob/ob mice as GSH/GSSG ratio was decreased (n = 4; P = 0.02). Whereas XOR activity measured by Amplex Red fluorescence was increased (n = 8; P = 0.04), XOR and NADPH oxidase subunits protein abundance were not changed in ob/ob mice (n = 6). Leptin deficiency did not disrupt NOS1 subcellular localization, as NOS1 co-localized with ryanodine receptor but not with caveolin-3. in conclusion, leptin deficiency is linked to decreased cardiac expression of NOSI and NO production, with a concomitant increase in XOR activity and oxidative stress, resulting in nitroso-redox imbalance. These data offer novel insights into potential mechanisms of myocardial dysfunction in obesity. (c) 2006 Elsevier Inc. All rights reserved.Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21205 USAUniversidade Federal de São Paulo, BR-04023062 São Paulo, BrazilUniv Miami, Miller Sch Med, Coral Gables, FL 33124 USAUniversidade Federal de São Paulo, EPM, BR-04023062 São Paulo, BrazilWeb of Scienc

Aging impairs the beneficial effect of granulocyte colony-stimulating factor and stem cell factor on post-myocardial infarction remodeling

Granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) are potential new therapies to ameliorate post-myocardial infarction (post-MI) remodeling, as they enhance endogenous cardiac repair mechanisms and decrease cardiomyocyte apoptosis. Because both of these pathways undergo alterations with increasing age, we hypothesized that therapeutic efficacy of G-CSF and SCF is impaired in old versus young adult rats. MI was induced in 6- and 20-month-old rats by permanent ligation of the left coronary artery. In young animals, G-CSF/SCF therapy stabilized and reversed a decline in cardiac function, attenuated left ventricular dilation, decreased infarct size, and reduced cardiomyocyte hypertrophy. Remarkably, these effects on cardiac structure and function were absent in aged rodents. This could not be attributed to ineffective mobilization of bone marrow cells or decreased quantity of c-Kit cells within the myocardium with aging. However, whereas the G-CSF/SCF cocktail reduced cardiac myocyte apoptosis in old as well as in young hearts, the degree of reduction was substantially less with age and the rate of cardiomyocyte apoptosis in old animals remained high despite cytokine treatment. These findings demonstrate that G-CSF/SCF lacks therapeutic efficacy in old animals by failing to offset periinfarct apoptosis and therefore raise important concerns regarding the efficacy of novel cytokine therapies in elderly individuals at greatest risk for adverse consequences of MI. © 2006 American Heart Association, Inc

Chronic allopurinol administration ameliorates maladaptive alterations in Ca2+ cycling proteins and beta-adrenergic hyporesponsiveness in heart failure

Xanthine oxidase (XO) activity contributes to both abnormal excitation-contraction (EC) coupling and cardiac remodeling in heart failure (HF). beta-Adrenergic hyporesponsiveness and abnormalities in Ca(2+) cycling proteins are mechanistically linked features of the HF phenotype. Accordingly, we hypothesized that XO influences beta-adrenergic responsiveness and expression of genes whose products participate in deranged EC coupling. We measured inotropic (dP/dt(max)), lusitropic (tau), and vascular (elastance; E(a)) responses to beta-adrenergic (beta-AR) stimulation with dobutamine in conscious dogs administered allopurinol (100 mg po daily) or placebo during a 4-wk induction of pacing HF. With HF induction, the decreases in both baseline and dobutamine-stimulated inotropic responses were offset by allopurinol. Additionally, allopurinol converted a vasoconstrictor effect to dobutamine to a vasodilator response and enhanced both lusitropic and preload reducing effects. To assess molecular correlates for this phenotype, we measured myocardial sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA), phospholamban (PLB), phosphorylated PLB (P-PLB), and Na(+)/Ca(2+) transporter (NCX) gene expression and protein. Although SERCA mRNA and protein concentrations did not change with HF, both PLB and NCX were upregulated (P < 0.05). Additionally, P-PLB and protein kinase A activity were greatly reduced. Allopurinol ameliorated all of these molecular alterations and preserved the PLB-to-SERCA ratio. Preventing maladaptive alterations of Ca(2+) cycling proteins represents a novel mechanism for XO inhibition-mediated preservation of cardiac function in HF, raising the possibility that anti-oxidant therapies for HF may ameliorate transcriptional changes associated with adverse cardiac remodeling and beta-adrenergic hyporesponsiveness