Cardiovascular Changes Related to Metabolic Syndrome: Evidence in Obese Zucker Rats

Martinelli, Ilenia; Tomassoni, Daniele; Moruzzi, Michele; Roy, Proshanta; Cifani, Carlo; Amenta, Francesco; Tayebati, Seyed Khosrow

doi:10.3390/ijms21062035

Cited by 30 publications

(48 citation statements)

References 71 publications

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“…This hypothesis is supported by the findings of latent hyperglycemia [51], hypercholesterolemia [52], and oxidative stress [53] occurring in OZRs since the 12th week of age. Indeed, our results demonstrate a conditions of oxidative stress in brain area, related to the imbalance of antioxidant and pro-oxidant pathways, as demonstrated in the blood and the heart of OZRs [42].…”

Section: Discussionsupporting

confidence: 61%

“…Based on these data, in our study, we sacrificed the rats at 12 weeks of age, when the OZRs established a condition of hyperphagia and body weight gain, but not yet the presence of overt hypertension. The difference in terms of blood pressure is not significant among the younger animals, but it was growing in obese condition, until reaching significance in 16-weeks-old OZRs [42].…”

Section: Discussionmentioning

confidence: 86%

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Obesity and Age-Related Changes in the Brain of the Zucker Lepr fa/fa Rats

et al. 2020

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Metabolic syndrome (MetS) is an association between obesity, dyslipidemia, hyperglycemia, hypertension, and insulin resistance. A relationship between MetS and vascular dementia was hypothesized. The purpose of this work is to investigate brain microanatomy alterations in obese Zucker rats (OZRs), as a model of MetS, compared to their counterparts lean Zucker rats (LZRs). 12-, 16-, and 20-weeks-old male OZRs and LZRs were studied. General physiological parameters and blood values were measured. Immunochemical and immunohistochemical techniques were applied to analyze the brain alterations. The morphology of nerve cells and axons, astrocytes and microglia were investigated. The blood–brain barrier (BBB) changes occurring in OZRs were assessed as well using aquaporin-4 (AQP4) and glucose transporter protein-1 (GLUT1) as markers. Body weight gain, hypertension, hyperglycemia, and hyperlipidemia were found in OZRs compared to LZRs. In the frontal cortex and hippocampus, a decrease of neurons was noticeable in the older obese rats in comparison to their age-matched lean counterparts. In OZRs, a reduction of neurofilament immunoreaction and gliosis was observed. The BBB of older OZRs revealed an increased expression of AQP4 likely related to the development of edema. A down-regulation of GLUT1 was found in OZRs of 12 weeks of age, whereas it increased in older OZRs. The behavioral analysis revealed cognitive alterations in 20-week-old OZRs. Based on these results, the OZRs may be useful for understanding the mechanisms through which obesity and related metabolic alterations induce neurodegeneration.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 86%

Obesity and Age-Related Changes in the Brain of the Zucker Lepr fa/fa Rats

et al. 2020

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“…MetSy was considered as an intermediate trait in the progression of severe cardiovascular disease (CVD) [ 8 , 9 ] and can contribute to the risk of diabetes[ 10 , 11 ]. However, obesity is an important component of metabolic syndrome that can independently contribute to the remaining components [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Body roundness index is a superior indicator to associate with the cardio‐metabolic risk: evidence from a cross‐sectional study with 17,000 Eastern-China adults

Zhang

et al. 2021

BMC Cardiovasc Disord

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Background To investigate the ability of body shape index (ABSI), body roundness index (BRI), waist circumference (WC), body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), and body adiposity index (BAI) for predicting non-adipose cardio-metabolic risk. Methods A total of 17,360 Chinese subjects aged 18–95 years old who escaped cardiovascular disease (CVD) or diabetes were recruited in the cross-sectional study. Anthropometric and biochemical parameters were assessed. Receiver operating characteristic curve (ROC) and multinomial logistic regression were conducted to examine the association of anthropometric indicators with cardio-metabolic risk factors. Results The mean age of subjects were 53.7(13.1) years, 41.6 % were males. The areas under the curve (AUC) demonstrated that WC, BMI, WHR, WHtR and BRI were able to predict high cardio-metabolic risk (AUC > 0.70). Meanwhile, multinomial logistic regression showed BRI was significantly associated with high cardio-metabolic risk (OR 3.27, 95% CI 3.01–3.55). The optimal cut-off values of BRI for high cardio-metabolic risk were (< 60 y: 3.49 vs. ≥60 y: 3.46) in males and (< 60 y: 3.47 vs. ≥60 y: 3.60) in females. Conclusions WC, BMI WHR, and WHtR were potential obesity indicators in discriminating high cardio-metabolic risk, while BAI or ABSI was not. Moreover, BRI revealed superior predictive capacity and significant association with accumulated cardio-metabolic risk factors.

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“…Second, we used ZO rats that are considered somewhat older (26 weeks) compared to the studies performed in younger animals. However, we have evaluated renal protection by these three drugs in a companion paper [ 16 ] and renal injury is usually manifested a few weeks later than the earliest manifestation of DD in these ZO rats [ 56 , 82 ].…”

Section: Discussionmentioning

confidence: 99%

Sacubitril/valsartan inhibits obesity-associated diastolic dysfunction through suppression of ventricular-vascular stiffness

Aroor

Mummidi

López-Alvarenga

et al. 2021

Cardiovasc Diabetol

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Objective Cardiac diastolic dysfunction (DD) and arterial stiffness are early manifestations of obesity-associated prediabetes, and both serve as risk factors for the development of heart failure with preserved ejection fraction (HFpEF). Since the incidence of DD and arterial stiffness are increasing worldwide due to exponential growth in obesity, an effective treatment is urgently needed to blunt their development and progression. Here we investigated whether the combination of an inhibitor of neprilysin (sacubitril), a natriuretic peptide-degrading enzyme, and an angiotensin II type 1 receptor blocker (valsartan), suppresses DD and arterial stiffness in an animal model of prediabetes more effectively than valsartan monotherapy. Methods Sixteen-week-old male Zucker Obese rats (ZO; n = 64) were assigned randomly to 4 different groups: Group 1: saline control (ZOC); Group 2: sacubitril/valsartan (sac/val; 68 mg•kg−1•day−1; ZOSV); Group 3: valsartan (31 mg•kg−1•day−1; ZOV) and Group 4: hydralazine, an anti-hypertensive drug (30 mg•kg−1•day−1; ZOH). Six Zucker Lean (ZL) rats that received saline only (Group 5) served as lean controls (ZLC). Drugs were administered daily for 10 weeks by oral gavage. Results Sac/val improved echocardiographic parameters of impaired left ventricular (LV) stiffness in untreated ZO rats, without altering the amount of food consumed or body weight gained. In addition to improving DD, sac/val decreased aortic stiffness and reversed impairment in nitric oxide-induced vascular relaxation in ZO rats. However, sac/val had no impact on LV hypertrophy. Notably, sac/val was more effective than val in ameliorating DD. Although, hydralazine was as effective as sac/val in improving these parameters, it adversely affected LV mass index. Further, cytokine array revealed distinct effects of sac/val, including marked suppression of Notch-1 by both valsartan and sac/val, suggesting that cardiovascular protection afforded by both share some common mechanisms; however, sac/val, but not val, increased IL-4, which is increasingly recognized for its cardiovascular protection, possibly contributing, in part, to more favorable effects of sac/val over val alone in improving obesity-associated DD. Conclusions These studies suggest that sac/val is superior to val in reversing obesity-associated DD. It is an effective drug combination to blunt progression of asymptomatic DD and vascular stiffness to HFpEF development in a preclinical model of obesity-associated prediabetes.

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Cardiovascular Changes Related to Metabolic Syndrome: Evidence in Obese Zucker Rats

Cited by 30 publications

References 71 publications

Obesity and Age-Related Changes in the Brain of the Zucker Lepr fa/fa Rats

Obesity and Age-Related Changes in the Brain of the Zucker Lepr fa/fa Rats

Body roundness index is a superior indicator to associate with the cardio‐metabolic risk: evidence from a cross‐sectional study with 17,000 Eastern-China adults

Sacubitril/valsartan inhibits obesity-associated diastolic dysfunction through suppression of ventricular-vascular stiffness

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