Atorvastatin Restores Endothelial Function in Offspring of Protein-Restricted Rats in a Cholesterol-Independent Manner

Abstract

Abstract-Maternal protein restriction in rats leads to endothelial dysfunction and decreased NO bioavailability in the offspring. Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) are recognized to have pleiotropic actions including increasing NO bioavailability and reducing inflammation and oxidative damage. This study assessed statin treatment on vascular function in a model of endothelial dysfunction, which is independent of dyslipidemia. Wistar rats were fed a control (18% casein) or protein-restricted (9% casein) diet throughout pregnancy. At weaning, a subset of the protein-restricted group was given atorvastatin (10 mg/kg per day) in the drinking water. At 145 days of age, offspring were euthanized by CO 2 inhalation. Plasma samples were collected for markers of inflammation, vascular reactivity of the thoracic aorta, and small mesenteric arteries were assessed on the wire myograph, and tissues were snap frozen for molecular biology analysis. Thoracic aorta endothelial-dependent vasodilatation was attenuated in the male offspring from both protein-restricted groups compared with controls (PϽ0.05) but was similar in females (P value not significant). Endothelial-dependent dilatation of mesenteric arteries was attenuated in male and female protein-restricted offspring (PϽ0.05) and was corrected by atorvastatin. Maternal protein restriction increased plasma inflammatory markers granulocyte chemotactic protein, lipocalin-2, and ␤ 2 -microglobulin in male and C-reactive protein in female offspring (PϽ0.05). Atorvastatin had no effect on inflammatory markers in the males but restored C-reactive protein to control levels in the females (PϽ0.05). Aortic and mesenteric artery mRNA levels of endothelial NO synthase, superoxide dismutase 1, and tumor necrosis factor-␣ were unchanged. These data suggest that atorvastatin can restore endothelial function in this model, but its effects are gender specific and dependent on the vascular bed. Key Words: statins (atorvastatin) Ⅲ experimental models Ⅲ fetal programming Ⅲ vascular biology Ⅲ endothelium Ⅲ nitric oxide Ⅲ inflammation T here is considerable evidence that the etiology of cardiovascular and metabolic diseases has origins partly in the developmental environment. 1 A widely used animal model to study this phenomenon is the rat, in which the restriction of dietary protein during pregnancy leads to raised blood pressure and endothelial dysfunction in the offspring. [2][3][4] Increasingly, evidence from this model points to a disruption to the NO pathway as a key component of the underlying pathophysiology. 4,5 The healthy vascular endothelium plays an important role in maintaining vascular tone through the release of factors including NO, prostacyclin, and endothelial-derived hyperpolarizing factor. 6 The importance of a healthy endothelium is seen in cardiovascular and metabolic diseases, where endothelial dysfunction is associated with atherosclerosis, hypertension, and the metabolic syndrome. 7-9 Important in the development of such endothelial ...

Statins prevent adverse effects of postnatal glucocorticoid therapy on the developing brain in rats

“…intermediate level between clinical studies and doses used in previous animal experiments (36,37). Body weight was recorded from P0 to P7 and every other day thereafter.…”

Hypercholesterolaemia, signs of islet microangiopathy and altered angiogenesis precede onset of type 2 diabetes in the Goto–Kakizaki (GK) rat

“…programming might strongly affect organ development and function [15][16][17] and GK rats present deficient beta cell mass from fetal life onwards [10,11]. Rat islet endothelial proliferation is very high around birth but declines rapidly during the first week postpartum [12].…”

“…Indeed, vessel development, a major component of pancreatic islet development and function, is particularly active around birth [12][13][14] and altered programming of vascularisation has been shown to affect the development and function of various organs [15][16][17].…”

Long-Term Statin Administration to Dams on High-Fat Diet Protects Not Only Them but Also Their Offspring from Cardiovascular Risk

“…There is much evidence in the literature showing that maternal nutrition either in terms of undernutrition (reduced calorie, protein or micronutrient content) or overnutrition [typified by a high-fat (HF) or high glycemic index diet] has a profound effect on the developing fetus via in utero mechanisms [1,2,3]. Critical to our understanding of the impact of an HF diet on cardiovascular disease (CVD) susceptibility is the response of key metabolic mechanisms to such a dietary challenge [4,5].…”