Characterization of a new animal model of metabolic syndrome: the DahlS.Z-Leprfa/Leprfa rat

Hattori, Takuya; Murase, Tatsuro; Ohtake, Masafumi; Inoue, Taku; Tsukamoto, Hide; Takatsu, Miwa; Kato, Yosuke; Hashimoto, Kimiko; Murohara, Toyoaki; Nagata, Kazuya

doi:10.1038/nutd.2010.1

Cited by 40 publications

(45 citation statements)

References 32 publications

(34 reference statements)

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“…9 As a result, the cardiac phenotype in female DS/obese rats has been found to be qualitatively similar to that of male DS/obese rats.…”

Section: Discussionmentioning

confidence: 62%

“…In addition, they develop cardiac hypertrophy as well as renal and liver damage, which may be responsible for their premature death. 9 These observations suggested that salt sensitivity of blood pressure and target organ damage are enhanced in MetS.…”

Section: Introductionmentioning

confidence: 88%

“…9 In addition, female DS/ obese rats developed LV hypertrophy, fibrosis and diastolic dysfunction as well as cardiac oxidative stress and inflammation. Both lowrenin hypertension with relative aldosterone excess and activation of the cardiac RAAS may have contributed to cardiac remodeling and diastolic dysfunction in these animals.…”

Section: Discussionmentioning

confidence: 99%

“…24 In the present study, however, SBP was higher in DS/obese rats than in DS/lean rats and in Zucker fatty rats at 11 weeks and thereafter, suggesting that the presence of the fa allele of Lepr on the DahlS background is associated with increased salt sensitivity of blood pressure, which may contribute to the development of cardiovascular complications and premature death within shorter period than in Zucker fatty rats. 9,25 The arterial pressure control mechanism of diuresis and natriuresis appears to be shifted toward higher blood pressure levels in obese individuals. 26 The elevation of SBP in DS/ obese rats was also accompanied by the increases in both homeostasis model assessment-insulin resistance and cardiac inflammatory responses, consistent with the concept that insulin resistance and inflammation may give rise to an altered profile of vascular function and thereby lead to hypertension.…”

Section: Discussionmentioning

confidence: 99%

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Cardiac remodeling and diastolic dysfunction in DahlS.Z-Leprfa/Leprfa rats: a new animal model of metabolic syndrome

et al. 2011

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We recently characterized male DahlS.Z-Lepr fa /Lepr fa (Dahl salt-sensitive (DS)/obese) rats, which were established from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome (MetS). We have now investigated cardiac pathophysiology and metabolic changes in female DS/obese rats in comparison with homozygous lean female littermates (DahlS.Z-Lepr + /Lepr + , or DS/lean, rats). Animals were maintained on a normal diet and were subjected to echocardiography followed by various pathological analyses at 15 weeks of age. Systolic blood pressure was significantly higher in female DS/obese rats than in DS/lean females at 12 weeks of age and thereafter. The survival rate of DS/obese rats was significantly lower than that of DS/lean rats at 15 weeks. Body weight, as well as visceral and subcutaneous fat mass were significantly increased in DS/obese rats, which also manifested left ventricular (LV) diastolic dysfunction and marked LV hypertrophy and fibrosis. In addition, myocardial oxidative stress and inflammation were increased in DS/obese rats compared with DS/lean rats. Serum insulin and triglyceride levels as well as the ratio of low-density lipoprotein-to high-density lipoprotein-cholesterol levels were markedly elevated in DS/obese rats, whereas fasting serum glucose concentrations were similar in the two rat strains. The phenotype of female DS/obese rats is similar to that of MetS in humans. These animals also develop salt-sensitive hypertension and LV diastolic dysfunction as well as LV hypertrophy and fibrosis, and these changes are associated with increased cardiac oxidative stress and inflammation. Keywords: cardiac hypertrophy; diastolic dysfunction; metabolic syndrome; myocardial fibrosis; salt-sensitive hypertension INTRODUCTION Metabolic syndrome (MetS), a complex of highly debilitating disorders including hypertension, diabetes mellitus and dyslipidemia, is associated with the development of visceral obesity. 1 Adipocytes in visceral fat of obese humans secrete a variety of biological agents that are known as adipocytokines and include proinflammatory cytokines such as tumor necrosis factor (TNF)-a and interleukin (IL)-6 as well as angiotensinogen and leptin. 2 Recent studies have revealed intricate interactions among adipocytes, the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) that contribute to the disturbed metabolic state associated with obesity. 3 Indeed, adipose tissue is thought to have an important role in the development of both hypertension and other complications related to insulin resistance. Activation of the RAAS and associated oxidative stress can result in mitochondrial abnormalities, altered bioenergetics and the accumulation of lipids in the heart, and thereby increase susceptibility to metabolic cardiomyopathy. 4

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“…9 As a result, the cardiac phenotype in female DS/obese rats has been found to be qualitatively similar to that of male DS/obese rats.…”

Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Cardiac remodeling and diastolic dysfunction in DahlS.Z-Leprfa/Leprfa rats: a new animal model of metabolic syndrome

et al. 2011

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“…In addition, they develop cardiac hypertrophy, as well as renal and liver damage, conditions that may be responsible for their premature death. 16 These observations suggested that salt sensitivity of blood pressure and target organ damage are enhanced in MetS. We have also shown that female DS/obese rats develop salt-sensitive hypertension, as well as left ventricular (LV) diastolic dysfunction, hypertrophy, and fibrosis, and that these conditions are accompanied by increased cardiac oxidative stress and inflammation.…”

mentioning

confidence: 65%

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

Murase

Hattori²,

Ohtake³

et al. 2012

Hypertension

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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...

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

Ito

Sano

Nagasawa

et al. 2016

Obesity Science & Practice

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SummaryIntroductionn‐3 Polyunsaturated fatty acids such as eicosapentaenoic acid (EPA), which are abundant in fish oil, have been shown to delay the onset of cardiovascular events. We previously established DahlS.Z‐Lepr fa/Lepr fa (DS/obese) rats, which are derived from a cross between Dahl salt‐sensitive and Zucker rats, as a model of metabolic syndrome. This study has now explored the influence of highly purified EPA on cardiac and adipose tissue pathophysiology in this animal model.Materials and methodsDS/obese rats were administered EPA (300 or 1,000 mg kg−1 d−1, per os) or vehicle from age 9 to 13 weeks. Homozygous lean (DahlS.Z‐Lepr +/Lepr +, or DS/lean) littermates were studied as controls.ResultsWhereas EPA had no effect on body weight, food intake or systolic blood pressure in DS/obese rats, it attenuated cardiac fibrosis, diastolic dysfunction, oxidative stress and inflammation in these animals. In addition, EPA did not affect insulin resistance but reduced adipocyte hypertrophy and inflammation in visceral fat of DS/obese rats. Moreover, EPA increased circulating levels of adiponectin as well as attenuated both the down‐regulation of AMP‐activated protein kinase phosphorylation and the up‐regulation of phosphorylation of the p65 subunit of nuclear factor‐kB in the heart of DS/obese rats.ConclusionsTreatment of DS/obese rats with EPA did not affect hypertension but reduced cardiac fibrosis and diastolic dysfunction, with the latter effects being accompanied by AMP‐activated protein kinase activation and inactivation of nuclear factor‐kB signalling in the heart, possibly as a result of an increase in adiponectin secretion. EPA may be suitable for the treatment of cardiac injury associated with metabolic syndrome.

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Characterization of a new animal model of metabolic syndrome: the DahlS.Z-Leprfa/Leprfa rat

Cited by 40 publications

References 32 publications

Cardiac remodeling and diastolic dysfunction in DahlS.Z-Leprfa/Leprfa rats: a new animal model of metabolic syndrome

Cardiac remodeling and diastolic dysfunction in DahlS.Z-Leprfa/Leprfa rats: a new animal model of metabolic syndrome

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

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

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Characterization of a new animal model of metabolic syndrome: the DahlS.Z-Leprfa/Leprfa rat

Cited by 40 publications

References 32 publications

Cardiac remodeling and diastolic dysfunction in DahlS.Z-Leprfa/Leprfa rats: a new animal model of metabolic syndrome

Cardiac remodeling and diastolic dysfunction in DahlS.Z-Leprfa/Leprfa rats: a new animal model of metabolic syndrome

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

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

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