Hyperlipidaemia induced by a high-cholesterol diet leads to the deterioration of guanosine-3′,5′-cyclic monophosphate/protein kinase G-dependent cardioprotection in rats

Background and purpose:

Hyperlipidaemia interferes with cardioprotective mechanisms, but the cause of this phenomenon is largely unknown, although hyperlipidaemia impairs the cardioprotective NO–cGMP system. However, it is not known if natriuretic peptide–cGMP–protein kinase G (PKG) signalling is affected by hyperlipidaemia. Therefore, we investigated the cardioprotective efficacy of cGMP-elevating agents in hearts from normal and hyperlipidaemic rats.

Experimental approach:

Male Wistar rats were rendered hyperlipidaemic by feeding with 2% cholesterol-enriched chow for 12 weeks. Hearts isolated from normal and hyperlipidaemic rats were perfused (Langendorff mode) and subjected to 30 min occlusion of the left main coronary artery, followed by 120 min reperfusion. 8-Br-cGMP (CG, 10 nM), B-type natriuretic peptide-32 (BNP, 10 nM), S-nitroso-N-acetyl-penicillamine (SNAP, 1 µM) were perfused from 10 min prior to coronary occlusion until the 15th min of reperfusion. Infarct size (% of ischaemic risk zone) was determined by triphenyltetrazolium staining.

Key results:

Treatment with CG, SNAP or BNP decreased infarct size significantly in normal hearts from its control value of 41.6 ± 2.9% to 15.5 ± 2.4%, 23.3 ± 3.0% and 25.3 ± 4.6%, respectively (P < 0.05). Protection by BNP was abolished by co-perfusion of PKG inhibitors KT5823 (600 nM) or Rp-8pCPT-PET-cGMPs (1 µM), confirming its PKG dependence. In hearts from hyperlipidaemic rats, CG, SNAP or BNP failed to decrease infarct size. Hyperlipidaemia did not alter basal myocardial PKG content, but decreased its activity as assessed by phosphorylation of cardiac troponin I.

Conclusions and implications:

This is the first demonstration that defects in the cardioprotective cGMP–PKG system could be a critical biochemical anomaly in hyperlipidaemia.     

Fish consumption,bone mineral density,and risk of hip fracture among older adults: The cardiovascular health study

Marine n‐3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may be beneficial for bone health, but few studies have investigated the association with fish consumption. Our aim was to study associations of fish and EPA + DHA consumption with bone mineral density (BMD) and hip fracture risk and determine whether high linoleic acid (LA) intake, the major dietary n‐6 PUFA, modifies the associations. The study population consisted of 5045 participants aged 65 years and older from the Cardiovascular Health Study. Data on BMD were available for 1305 participants. Food‐frequency questionnaire was used to assess dietary intake, and hip fracture incidence was assessed prospectively by review of hospitalization records. After multivariable adjustment, femoral neck BMD was 0.01 g/cm² lower in the highest versus lowest tuna/other‐fish intake category (p = .05 for trend). EPA + DHA intake (higher versus lower median of 0.32 g/day) was associated with lower femoral neck BMD (0.66 versus 0.71 g/cm², p < .001) among those with LA intake greater than the median 12.1 g/day (p = .03 for interaction). No significant associations were found with total‐hip BMD. During mean follow‐up of 11.1 years, 505 hip fractures occurred. Fish or EPA + DHA consumption was not significantly associated with fracture incidence [hazard ratio (HR) for extreme categories: HR = 1.23, 95% confidence interval (CI) 0.83–1.84 for tuna/other fish; HR = 1.16, 95% CI 0.91–1.49 for fried fish; and HR = 0.98, 95% CI 0.71–1.36 for EPA + DHA]. High LA intake did not modify these associations. In this large prospective cohort of older adults, fish consumption was associated with very small differences in BMD and had no association with hip fracture risk. © 2010 American Society for Bone and Mineral Research.     

Decreased levels of the potent regulator of monocyte/macrophage activation, interleukin-13, in the peritoneal fluid of patients with endometriosis

Endometriosis is characterized by an increase in the number, activation and secretory activity of peritoneal fluid macrophages. Factors regulating the activation of these cells may be important in the pathophysiology of this disease. In this study we measured by enzyme- linked immunosorbent assay the concentrations of the macrophage inhibitory factor interleukin (IL)-13 in the peritoneal fluid of women with and without endometriosis. It was found that women with endometriosis had significantly lower amounts of IL-13 (95 +/- 9.8 pg/ml) in peritoneal fluid, compared with women without endometriosis (115 +/- 30 pg/ml) (P < 0.01). No cycle-specific variation was evident for either group. Another macrophage inhibitory interleukin (IL-10) was also measured, but no differences between women with (16.1 +/- 13.2 pg/ml) or without (10.3 +/- 5.6 pg/ml) endometriosis were seen. The immunolocalization of IL-13 was assessed in eutopic and ectopic endometrium and in isolated peritoneal fluid cells. Glandular epithelial cells and stromal cells in both eutopic and ectopic endometrium were immunopositive for IL-13. No cycle-specific differences in the immunolocalization of IL-13 were seen. In conclusion, the reduced amounts of IL-13 in the peritoneal fluid of women with endometriosis may lead to a lack of suppression of macrophage activation, thereby contributing to the overall pathogenesis of this disease.