Cardiovascular, Metabolic and Inflammatory Changes after Ovariectomy and Estradiol Substitution in Hereditary Hypertriglyceridemic Rats.

BACKGROUND: If menopause is really independent risk factor for cardiovascular disease is still under debate. We studied if ovariectomy in the model of insulin resistance causes cardiovascular changes, to what extent are these changes reversible by estradiol substitution and if they are accompanied by changes in other organs and tissues. METHODS: Hereditary hypertriglyceridemic female rats were divided into three groups: ovariectomized at 8th week (n = 6), ovariectomized with 17-ß estradiol substitution (n = 6), and the sham group (n = 5). The strain of abdominal aorta measured by ultrasound, expression of vascular genes, weight and content of myocardium and also non-cardiac parameters were analyzed. RESULTS: After ovariectomy, the strain of abdominal aorta, expression of nitric oxide synthase in abdominal aorta, relative weight of myocardium and of the left ventricle and circulating interleukin-6 decreased; these changes were reversed by estradiol substitution. Interestingly, the content of triglycerides in myocardium did not change after ovariectomy, but significantly increased after estradiol substitution while adiposity index did not change after ovariectomy, but significantly decreased after estradiol substitution. CONCLUSION: Vascular and cardiac parameters under study differed in their response to ovariectomy and estradiol substitution. This indicates different effects of ovariectomy and estradiol on different cardiovascular but also extracardiac structures.

Deleterious Effects of Hyperactivity of the Renin-Angiotensin System and Hypertension on the Course of Chemotherapy-Induced Heart Failure after Doxorubicin Administration: A Study in Ren-2 Transgenic Rat.

Doxorubicin's (DOX) cardiotoxicity contributes to the development of chemotherapy-induced heart failure (HF) and new treatment strategies are in high demand. The aim of the present study was to characterize a DOX-induced model of HF in Ren-2 transgenic rats (TGR), those characterized by hypertension and hyperactivity of the renin-angiotensin-aldosterone system, and to compare the results with normotensive transgene-negative, Hannover Sprague-Dawley (HanSD) rats. DOX was administered for two weeks in a cumulative dose of 15 mg/kg. In HanSD rats DOX administration resulted in the development of an early phase of HF with the dominant symptom of bilateral cardiac atrophy demonstrable two weeks after the last DOX injection. In TGR, DOX caused substantial impairment of systolic function already at the end of the treatment, with further progression observed throughout the experiment. Additionally, two weeks after the termination of DOX treatment, TGR exhibited signs of HF characteristic for the transition stage between the compensated and decompensated phases of HF. In conclusion, we suggest that DOX-induced HF in TGR is a suitable model to study the pathophysiological aspects of chemotherapy-induced HF and to evaluate novel therapeutic strategies to combat this form of HF, which are urgently needed.

Links between macrophages in perivascular adipose tissue and arterial wall: a role in atherosclerosis initiation?

BACKGROUND: Inflammation of adipose tissue in relation to atherosclerosis is currently widely studied in patients with advanced disease. However, data regarding polarization of adipose tissue and arterial wall macrophages and their mutual link in the early stages of atherosclerosis are scarce. The main aim of this cross-sectional study was to characterize macrophage subpopulations in arterial wall and adjacent adipose tissue; and to determine links between different subpopulations in a relatively healthy population living kidney donors. METHODS: The presence of cardiovascular risk factors was established in 68 living kidney donors. Macrophage polarization was analyzed by flow cytometry and confirmed by RT-PCR in samples of visceral adipose tissue, renal artery and adjacent perivascular adipose tissue collected during hand-assisted retroperitoneoscopic nephrectomy. RESULTS: CD14+CD16+CD36high macrophages were found only in adipose tissues and were strongly positively associated with several cardiovascular risk factors. The CD14+CD16+CD36low subpopulation was positively associated with the presence of several cardiovascular risk factors to a lesser extent in all studied tissues. In contrast, the proportion of CD14+CD16-CD36low macrophages was negatively linked to several cardiovascular risk factors and increased in subjects on statin therapy. The proportion of CD14+CD16+CD36low macrophages in perivascular, not visceral adipose tissue was associated with that of both macrophage subtypes in the arterial wall, suggesting a direct link between perivascular adipose tissue and the arterial wall. CONCLUSIONS: We confirmed the association of three macrophage subtypes in adipose tissue and arterial wall to the studied cardiovascular risk factors. Macrophage polarization in perivascular, but not visceral adipose tissue was linked to macrophage polarization in the arterial wall.

Rapid Drop in Coronary Heart Disease Mortality in Czech Male Population-What Was Actually behind It?

The high mortality of coronary heart disease (CHD) among Czech men-one of the highest worldwide-began to decline in 1991 soon after the abolition of government subsidies to all foodstuffs rich in animal fat. As participants in the WHO MONICA Project, we were able to analyze the CHD risk factors just before and after this major economic change. We had previously documented that the originally subsidized prices decreased animal fat consumption and consequently non-HDL cholesterol concentrations in the population. By the early 1990s, no progress had been made in the treatment of acute myocardial infarction, statins were unavailable as was not the currently more effective antihypertensive therapy. Our recent research proved a close relationship between cholesterolemia and proinflammatory macrophages in adipose tissue and accelerated macrophage polarization with increased palmitate and palmitoleate contents in cell membrane phospholipids. By contrast, the proportion of proinflammatory macrophages decreases with increasing presence of n-3 fatty acids in the cell membrane. The combination of non-HDL cholesterol drop and a decreased proportion of proinflammatory macrophages due to replacement of alimentary fat decreased CHD mortality immediately.

Statins Directly Influence the Polarization of Adipose Tissue Macrophages: A Role in Chronic Inflammation.

Statins represent one of the most widely used classes of drugs in current medicine. In addition to a substantial decrease in atherogenic low density lipoprotein (LDL) particle concentrations, several large trials have documented their potent anti-inflammatory activity. Based on our preliminary data, we showed that statins are able to decrease the proportion of pro-inflammatory macrophages (CD14+16+CD36high) in visceral adipose tissue in humans. In the present study including 118 healthy individuals (living kidney donors), a very close relationship between the pro-inflammatory macrophage proportion and LDL cholesterol levels was found. This was confirmed after adjustment for the most important risk factors. The effect of statins on the proportion of pro-inflammatory macrophages was also confirmed in an experimental model of the Prague hereditary hypercholesterolemia rat. A direct anti-inflammatory effect of fluvastatin on human macrophage polarization in vitro was documented. Based on modifying the LDL cholesterol concentrations, statins are suggested to decrease the cholesterol inflow through the lipid raft of macrophages in adipose tissue and hypercholesterolemia to enhance the pro-inflammatory macrophage phenotype polarization. On the contrary, due to their opposite effect, statins respond with anti-inflammatory activity, affecting the whole organism.