Effect of obesity reduction on preservation of heart function and attenuation of left ventricular remodeling, oxidative stress and inflammation in obese mice

Abstract

BackgroundObesity is an important cardiovascular risk factor. This study tested the effect of obesity reduction on preserving left ventricular ejection fraction (LVEF) and attenuating inflammation, oxidative stress and LV remodeling in obese mice.Methods and resultsEight-week-old C57BL/6 J mice (n=24) were equally divided into control (fed a control diet for 22 weeks), obesity (high-fat diet, 22 weeks), and obese reduction (OR) (high-fat diet, 14 weeks; then control diet, 8 weeks). Animals were sacrificed at post 22-week high-fat diet and the LV myocardium collected. Heart weight, body weight, abdominal-fat weight, total cholesterol level and fasting blood glucose were higher in obesity than in control and OR (all p<0.001). Inflammation measured by mRNA expressions of IL-6, MMP-9, PAI-1 and leptin and protein expression of NF-κB was higher, whereas anti-inflammation measured by mRNA expressions of adiponectin and INF-γ was lower in obesity than in control and OR (all p<0.003). Oxidative protein expressions of NOX-1, NOX-2 and oxidized protein were higher, whereas expression of anti-oxidant markers HO-1 and NQO-1 were lower (all p<0.01); and apoptosis measured by Bax and caspase 3 was higher, whereas anti-apoptotic Bcl-2 was lower in obesity as compared with control and OR (all p<0.001). The expressions of fibrotic markers phosphorylated Smad3 and TGF-β were higher, whereas expression of anti-fibrotic phosphorylated Smad1/5 and BMP-2 were lower (all p<0.02); and LVEF was lower, whereas the LV remodeling was higher in obesity than in control and OR (all p<0.001).ConclusionImpaired LVEF, enhanced LV remodeling, inflammation, fibrosis, oxidative stress and apoptosis were reversed by reduction in mouse obesity.

Oxidative Stress and Nerve Function After Cardiopulmonary Bypass in Patients With Diabetes

“…This observation is corroborated by previous studies that have shown the reduction in neurotransmitters and sympathetic nerves as a possible mechanism for neuropathy in diabetes [6]. Decreased nerve growth results in decreased NPY, which is considered the "master switch" for angiogenesis and cardiac remodeling under stress and ischemia [9,25].…”

Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities

“…Due to alterations in their metabolic and neurohumoral profile, these patients may have unique pathophysiologic defects in post-infarction repair. For example, overactive TGF-β/Smad signaling is often associated with insulin resistance, obesity and diabetes (7), (132) and may drive the reparative process towards a potent pro-fibrotic response. Identification of specific reparative defects in models of obesity and metabolic dysfunction and validation of these pathophysiologic alterations in obese patients with myocardial infarction using biomarkers or suitable imaging studies may result in design of specific therapeutic approaches to reduce adverse remodeling in these patients (133).…”

Redox regulation of insulin sensitivity due to enhanced fatty acid utilization in the mitochondria

“…Measures of protein glycation, a form of oxidative damage that can occur at high concentrations of sugars (34,38), have been shown to increase in serum and adipose tissue of mice or rats fed high-fat diets (53,79,90). In the heart, ob/ob mice have decreased levels of reduced glutathione (80), and mice fed a high-fat diet have increased levels of protein oxidation products (96). These observations indicate that high dietary fat and obesity induce a general state of oxidative stress and have often led to the conclusion that oxidative damage contributes to accompanying pathophysiological events including cardiovascular disease.…”