Murine models for pharmacological studies of the metabolic syndrome

Butcher

American Journal of Physiology-Heart and Circulatory Physiology

et al. 2016

-To determine the impact of progressive elevations in peripheral vascular disease (PVD) risk on microvascular function, we utilized eight rat models spanning "healthy" to "high PVD risk" and used a multiscale approach to interrogate microvascular function and outcomes: healthy: SpragueDawley rats (SDR) and lean Zucker rats (LZR); mild risk: SDR on high-salt diet (HSD) and SDR on high-fructose diet (HFD); moderate risk: reduced renal mass-hypertensive rats (RRM) and spontaneously hypertensive rats (SHR); high risk: obese Zucker rats (OZR) and Dahl salt-sensitive rats (DSS). Vascular reactivity and biochemical analyses demonstrated that even mild elevations in PVD risk severely attenuated nitric oxide (NO) bioavailability and caused progressive shifts in arachidonic acid metabolism, increasing thromboxane A 2 levels. With the introduction of hypertension, arteriolar myogenic activation and adrenergic constriction were increased. However, while functional hyperemia and fatigue resistance of in situ skeletal muscle were not impacted with mild or moderate PVD risk, blood oxygen handling suggested an increasingly heterogeneous perfusion within resting and contracting skeletal muscle. Analysis of in situ networks demonstrated an increasingly stable and heterogeneous distribution of perfusion at arteriolar bifurcations with elevated PVD risk, a phenomenon that was manifested first in the distal microcirculation and evolved proximally with increasing risk. The increased perfusion distribution heterogeneity and loss of flexibility throughout the microvascular network, the result of the combined effects on NO bioavailability, arachidonic acid metabolism, myogenic activation, and adrenergic constriction, may represent the most accurate predictor of the skeletal muscle microvasculopathy and poor health outcomes associated with chronic elevations in PVD risk. rodent models of cardiovascular disease risk; peripheral vascular disease; blood flow regulation; microvascular dysfunction; system biology of microcirculation NEW & NOTEWORTHY Linking peripheral vascular disease (PVD) risk to integrated microvascular dysfunction and health outcomes has been elusive. We used eight models of increasing risk and a multiscale approach to interrogate novel indexes of microvascular function, perfusion/oxygen handling, and outcomes. We demonstrate how elevated PVD risk leads to progressive microvascular "dampening," with clear implications for outcomes.THE PREDOMINANT CONCERN regarding the presence of peripheral vascular disease (PVD) risk factors of increasing severity is that these can lead to the development of pathological characteristics of PVD including myocardial infarction, heart failure, stoke, and/or limb ischemia. These potential outcomes of PVD result in elevations in mortality risk as well as significant reductions in quality of life through a variety of direct and indirect causes (3,45,50) that are predominantly perceived as macrovascular events. These global processes can develop across tissues and organs, leading to the clinica...

Section: Linking Peripheral Vascular Disease (Pvd) Risk To Integratedmentioning

confidence: 99%

Increased peripheral vascular disease risk progressively constrains perfusion adaptability in the skeletal muscle microcirculation

Butcher

American Journal of Physiology-Heart and Circulatory Physiology

et al. 2016

Journal of Endocrinology

“…Therefore, rat models are the most useful. Spontaneous mutations and selective breeding procedures in rats provide several complementary models of obesity, hyperlipidemia, insulin resistance, and type 2 diabetes, as well as cardiovascular diseases including hypertension (Russell & Proctor 2006, Fellmann et al 2013. Although each animal model has some limitations and strengths, used together in a complementary fashion they are essential for the research on metabolic and cardiovascular diseases.…”

Section: Rat Models Of Obesity and Hypertensionmentioning

confidence: 99%

“…Both rat and mouse strains susceptible to the development of obesity are fed a high-fat diet (HFD) over a period of 3-4 months (Vickers et al 2011, Fellmann et al 2013. Within rat strains, Wistar and Sprague-Dawley strains are most often used.…”

Section: Rat Models Of Obesity and Hypertensionmentioning

confidence: 99%

Obesity-related hypertension: possible pathophysiological mechanisms

Vaněčková¹,

Maletı́nská²,

Behuliak³

et al. 2014

129

Hypertension is one of the major risk factors of cardiovascular diseases, but despite a century of clinical and basic research, the discrete etiology of this disease is still not fully understood. The same is true for obesity, which is recognized as a major global epidemic health problem nowadays. Obesity is associated with an increasing prevalence of the metabolic syndrome, a cluster of risk factors including hypertension, abdominal obesity, dyslipidemia, and hyperglycemia. Epidemiological studies have shown that excess weight gain predicts future development of hypertension, and the relationship between BMI and blood pressure (BP) appears to be almost linear in different populations. There is no doubt that obesity-related hypertension is a multifactorial and polygenic trait, and multiple potential pathogenetic mechanisms probably contribute to the development of higher BP in obese humans. These include hyperinsulinemia, activation of the renin-angiotensin-aldosterone system, sympathetic nervous system stimulation, abnormal levels of certain adipokines such as leptin, or cytokines acting at the vascular endothelial level. Moreover, some genetic and epigenetic mechanisms are also in play. Although the full manifestation of both hypertension and obesity occurs predominantly in adulthood, their roots can be traced back to early ontogeny. The detailed knowledge of alterations occurring in the organism of experimental animals during particular critical periods (developmental windows) could help to solve this phenomenon in humans and might facilitate the age-specific prevention of human obesity-related hypertension. In addition, better understanding of particular pathophysiological mechanisms might be useful in so-called personalized medicine. Key Words" obesity " hypertension " sympathetic nervous system " renin-angiotensin system " critical developmental periods " epigenetics " rat

“…Obese Zucker rats are genetically predisposed to obesity and insulin resistance due to a mutation in the leptin receptor (fa/fa) [21,22]. Rats were ovariectomized at 5 weeks of age and held for 5 days to clear endogenous ovarian hormones.…”

Section: Animalsmentioning

confidence: 99%

“…Obese Zucker rats are genetically predisposed to obesity and insulin resistance due to a mutation in the leptin receptor (fa/fa) [21,22]. Lean Zucker rats (fa/fa) serve as controls in these experiments, and demonstrate normal insulin sensitivity.…”

Section: Cgrrf1 Expression Is Modulated In Vivo By Insulin Sensitizinmentioning

confidence: 99%

CGRRF1 as a novel biomarker of tissue response to metformin in the context of obesity

Zhang¹,

Schmandt²,

Celestino³

et al. 2014

Gynecologic Oncology

Objective-Obesity-associated hyperestrogenism and hyperinsulinemia contribute significantly to the pathogenesis of endometrial cancer. We recently demonstrated that metformin, a drug long used for treatment of type 2 diabetes, attenuates both insulin-and estrogen-mediated proliferative signaling in the obese rat endometrium. In this study, we sought to identify tissue biomarkers that may prove clinically useful to predict tissue response for both prevention and therapeutic studies. We identified CGRRF1 (Cell growth regulator with ring finger domain 1) as a novel metforminresponsive gene and characterized its possible role in endometrial cancer prevention.Methods-CGRRF1 mRNA expression was evaluated by RT-qPCR in the endometrium of obese and lean rats, and also in normal and malignant human endometrium. CGRRF1 levels were genetically manipulated in endometrial cancer cells, and its effects on proliferation and apoptosis were evaluated by MTT and western blot.Results-CGRRF1 is significantly induced by metformin treatment in the obese rat endometrium. In vitro studies demonstrate that overexpression of CGRRF1 inhibits endometrial cancer cell proliferation. Analysis of human endometrial tumors reveal that CGRRF1 expression is significantly lower in hyperplasia, Grade 1, Grade 2, Grade 3, MMMT, and UPSC endometrial Supplemental dataThe effect of p53 on CGRRF1 expression was evaluated by Western blot analysis in ECC-1 cells. Expression of p53 was silenced using p53 si RNA. Conclusion-CGRRF1 represents a novel, reproducible tissue marker of metformin response in the obese endometrium. Furthermore, our preliminary data suggests that up-regulation of CGRRF1 expression may prove clinically useful in the prevention or treatment of endometrial cancer. NIH Public Access