Effects of Estrogen on Cardiovascular Injury in Ovariectomized Female DahlS.Z- Lepr ^fa /Lepr ^fa Rats as a New Animal Model of Metabolic Syndrome

Abstract

Abstract-Although recent clinical trials have found an increased incidence of cardiovascular disease in women on estrogen replacement therapy, the underlying mechanism remains unclear. We have recently characterized DahlS.Z-Lepr fa /Lepr fa (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome. We have now examined the effects of estrogen replacement on cardiac pathophysiology in ovariectomized female DS/obese (Ovx-DS/obese) rats. Animals subjected to ovariectomy at 7 weeks of age were implanted subcutaneously with a 60-day release pellet containing 0.5 mg of 17␤-estradiol (E 2 ) or placebo at 8 weeks. Age-matched female homozygous lean littermates (DahlS.Z-Lepr ϩ /Lepr ϩ or DS/lean rats) of DS/obese rats served as controls. Animals were maintained on a normal diet and were subjected to echocardiography followed by various pathological analyses at 13 weeks of age. Ovx-DS/obese rats manifested hypertension at 7 weeks of age and thereafter and showed left ventricular (LV) fibrosis and diastolic dysfunction at 13 weeks. Treatment with E 2 attenuated hypertension in Ovx-DS/obese rats but had no effect on blood pressure in ovariectomized female DS/lean (Ovx-DS/lean) rats. E 2 treatment exacerbated LV fibrosis and diastolic dysfunction, as well as further increased cardiac oxidative stress and inflammation in Ovx-DS/obese rats, and it elicited similar effects in Ovx-DS/lean rats. E 2 reduced food intake, body weight, and visceral fat content in both Ovx-DS/obese and Ovx-DS/lean rats. E 2 treatment attenuated hypertension and obesity but exacerbated LV fibrosis and diastolic dysfunction in Ovx-DS/obese rats, with these latter effects being associated with increased cardiac oxidative stress and inflammation. (Hypertension. 2012;59:694-704.) • Online Data Supplement Key Words: metabolic syndrome Ⅲ estrogen Ⅲ hypertension Ⅲ myocardial fibrosis Ⅲ diastolic dysfunction Ⅲ oxidative stress Ⅲ inflammation M etabolic syndrome (MetS), a complex of highly debilitating disorders including hypertension, diabetes mellitus, and dyslipidemia, is associated with the development of visceral obesity. 1 MetS afflicts both men and women and increases the risk of heart disease in both sexes, although it appears to inflict a greater burden in women. The incidence of cardiovascular disease among women is low before menopause but steadily increases thereafter. 2 This increase is thought to result in part from the loss of endogenous estrogen and its associated cardioprotective effects. 3 A key issue faced by most postmenopausal women is the potential impact of estrogen replacement therapy on the prevalence of cardiovascular disease. Estrogen replacement in postmenopausal women has been associated with a reduced risk of cardiovascular disease. 4 However, the Heart and Estrogen/Progestin Replacement Study 5 and the Women's Health Initiative Study 6 do not support the notion that hormone replacement therapy protects the cardiovascular system but rather suggest the opposite vi...

Effects of pioglitazone on cardiac and adipose tissue pathology in rats with metabolic syndrome

“…Portions of the RNA (2 μg) were subjected to reverse transcription (RT) with the use of a PrimerScript RT Reagent Kit (Takara, Shiga, Japan). Quantitative PCR analysis was performed with the use of SYBR Mix Ex Taq II (Takara), a Thermal Cycler Dice Real Time System II (Takara), and specific primers for cDNAs encoding atrial natriuretic peptide (ANP) [13], brain natriuretic peptide (BNP) [13], collagen type I or type III [22], connective tissue growth factor (CTGF) [19], transforming growth factor-β1 (TGF-β1) [13], monocyte chemoattractant protein-1 (MCP-1) [19], osteopontin [19], cyclooxygenase-2 (COX-2) [23], TNF-α [12], angiotensin-converting enzyme (ACE) [13], the mineralocorticoid receptor (MR) [13], the glucocorticoid receptor (GR) (5 -GGAAAAGCCATCGTCAAAAGG-3 and 5 -TTCTCAACCACCTCATGCATG-3 as forward and reverse primers, respectively; GenBank accession no. NM_012576), 11β-HSD1 (5 -CTCTGCTCACTATATTGC-3 and 5 -GTCTGTCT CATGTCATTG-3 as forward and reverse primers, respectively; GenBank accession no.…”

Estrogen Replacement Therapy and Cardiac Function Under Metabolic Syndrome

“…6 Animals ovariectomized at 7 weeks of age received an estrogen pellet or placebo at 8 weeks. Age-matched female homozygous lean littermates (DahlS.Z-Leprϩ/Leprϩ or DS/lean rats) of DS/ obese rats served as controls.…”

Highly purified eicosapentaenoic acid ameliorates cardiac injury and adipose tissue inflammation in a rat model of metabolic syndrome

“…Total RNA was extracted from LV and visceral (retroperitoneal) fat tissue and was subjected to reverse transcription and real‐time polymerase chain reaction analysis as described with specific primers for cDNAs encoding atrial natriuretic peptide , brain natriuretic peptide , collagen type I or type III , connective tissue growth factor , transforming growth factor‐β1 , monocyte chemoattractant protein‐1 (MCP‐1) , osteopontin , cyclooxygenase‐2 (COX‐2) and the p22 phox , gp91 phox and Rac1 subunits of NADPH oxidase. Reagents for detection of human glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) mRNA (Applied Biosystems, Foster City, CA, USA) were used to quantify rat GAPDH mRNA as an internal standard.…”