A Sodium Glucose Cotransporter 2 Inhibitor Fails to Improve Perivascular Adipose Tissue-Mediated Modulation of Vasodilation and Cardiac Function in Rats With Metabolic Syndrome

Arterial perivascular adipose tissue (PVAT) can elicit vasodilator signals complementary to those elicited by the endothelium in SHRSP.Z- Leprfa/IzmDmcr (SHRSP.ZF) rats, an animal model of metabolic syndrome (MetS). Here, we tested whether a glucose cotransporter 2 inhibitor (SGLT2-i; tofogliflozin) increased this PVAT effect to prevent the deterioration of cardiac function in aging SHRSP.ZF rats. Tofogliflozin treatments (1 or 10 mg/kg/day) or vehicle (control) were administered for 10 weeks by oral gavage to SHRSP.ZF rats, starting at 13 weeks of age. At 23 weeks of age, glucose levels in the serum and urine (24 h after the last administration) were determined using commercial kits. Vasodilator responsiveness of PVAT-surrounded or PVAT-free superior mesenteric arteries was determined using acetylcholine with organ-bath methods. Cardiac ventricular function and coronary flow were determined using Langendorff heart preparations. Serum and urine glucose levels in SGLT2-i treatment groups did not differ from those in the controls, but the ratios of glycated to non-glycated albumin were lower than those in the controls. Tofogliflozin treatments did not alter relaxations in the presence of PVAT or affect relaxations of PVAT-free arteries. Left ventricular systolic pressures, maximum rate of pressure decline, and coronary flow in ex vivo hearts did not differ among the treatment groups. PVAT effects and cardiac dysfunction were not altered by tofogliflozin treatment in SHRSP.ZF rats with MetS. These results do not provide strong evidence to support the use of SGLT2-i as a cardiovascular protective therapy in MetS, which occurs prior to the onset of type 2 diabetes.

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Abstract P171: Comparison Of Modulation Of Renal Arterial Tone By Perivascular Adipose Tissue Between Two Animal Models Of Metabolic Syndrome

Hypertension ◽

10.1161/hyp.78.suppl_1.p171 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Satomi Kagota ◽

Kana Maruyama-Fumoto ◽

Kana Morikawa ◽

Kazumasa Shinozuka

Keyword(s):

Metabolic Syndrome ◽

Animal Model ◽

Sex Differences ◽

Adipose Tissue ◽

Female Rats ◽

Male Rats ◽

Organ Bath ◽

Perivascular Adipose Tissue ◽

Enhancing Effect ◽

Arterial Tone

Sex differences have recently been noticed in the regulation of arterial tone by perivascular adipose tissue (PVAT). In SHRSP.Z- Lepr fa /IzmDmcr (SHRSP.ZF) rats, an animal model of metabolic syndrome (MetS), we demonstrated that mesenteric and renal PVAT in female rats consistently have an enhancing effect on vasodilation at 23 weeks, an age by which the effect of PVAT is impaired in the male rats. This could explain the sex differences in the prevalence of cardiovascular complications in patients with MetS. Therefore, we determined whether the sex difference in PVAT response also occurs in another animal model of MetS, SHR/NDmcr-cp (SHR-cp) rats.Renal arteries were isolated from male and female 23-week-old SHR-cp rats, and ring preparations with and without PVAT were made. After a stable contraction was obtained by phenylephrine administration, vasodilation in response to acetylcholine was examined using organ bath methods.Vasodilation in arteries without PVAT from female rats was smaller than that in arteries without PVAT from male rats, and presence of PVAT in arteries from female rats increased vasodilation to the same level as that observed in arteries without PVAT from male rats. Furthermore, renal PVAT in male rats was shown to have an enhancing effect on vasodilation.The present study did not identify sex differences in renal PVAT-mediated modulation in SHR-cp rats because the enhancing effects of PVAT did not disappear in male SHR-cp rats, in contrast to that observed in male SHRSP.ZF rats at the same age. The difference in PVAT response in male rats between two MetS models may be due to differences in the severity of MetS symptoms, especially blood pressure, between the models.

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Abstract 3672: Loss of Perivascular Adipocyte Paracrine Function Leads to Increased Vascular Tone and Glucose Intolerance in Hypertension

Circulation ◽

10.1161/circ.118.suppl_18.s_463-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Kaivan Khavandi ◽

Adam Greenstein ◽

Sarah Withers ◽

Kazuhiko Sonoyama ◽

Sarah Lewis ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Vascular Tone ◽

Tnf Alpha ◽

Perivascular Adipose Tissue ◽

The Metabolic Syndrome ◽

Adipocyte Cell ◽

Therapeutic Opportunity

In order to investigate the contribution of perivascular adipose tissue (PVAT) to arterial function, a total of 55 small arteries harvested from 35 skin biopsies of patients with Metabolic Syndrome and matched controls were mounted as ring preparations in a wire myograph. Contractility to cumulative doses of Norepinephrine in the presence or absence of PVAT showed an anticontractile effect in arteries from healthy volunteers (p=0.009), which was lost in patients with Metabolic Syndrome. Bioassay studies confirmed that PVAT releases a hydrophilic anticontractile factor in health, which is absent in obesity. Using a soluble fragment of the human Type 1 receptor, we identified that the anticontractile factor was adiponectin, which is the sole mediator of vasodilation, acting by increasing endothelial bioavailability of nitric oxide. Significant endothelial dysfunction was observed in patients with Metabolic Syndrome (p<0.001). Quantitative image analysis of adipose tissue revealed significantly increased adipocyte cell size in patients with Metabolic Syndrome, compared with healthy controls (p<0.006). There was immunohistochemical evidence of inflammation with upregulation of TNF-alpha receptor 1 in these patients (p<0.001). Application of exogenous TNF-alpha abolished the anticontractile effect of PVAT by reducing adiponectin bioavailability. Oxidative stress also induced by cytokines TNF-alpha and IL-6 but not IL-1, reduced adiponectin production from PVAT and increased basal tone. When the obese microenvironment was replicated in vitro by inflicting hypoxia on PVAT, adiponectin activity was lost but then rescued by incubation with cytokine antagonists. Further application of the adiponectin receptor fragment abolished PVAT relaxation. We conclude that in healthy arteries, PVAT releases adiponectin which reduces vascular tone. In obesity, this is lost by a cascade of adipocyte hypertrophy, hypoxia, inflammation and oxidative stress. The resulting vasoconstriction contributes to hypertension, hypertriglyceridaemia and insulin resistance. Direct targeting of adiponectin release from PVAT therefore provides a novel therapeutic opportunity in the Metabolic Syndrome.

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Abstract 122: Cardiac mTOR Preserves Cardiac Function Following Ex Vivo Ischemia-Reperfusion in Diet-Induced Obese Mice

Circulation Research ◽

10.1161/res.111.suppl_1.a122 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Toshinori Aoyagi ◽

Takashi Matsui

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Cardiac Function ◽

Glucose Intolerance ◽

Ex Vivo ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Heart Weight ◽

Diabetic Patients ◽

Significant Difference

The risk of heart failure following myocardial infarction is higher in diabetic patients than nondiabetic patients. The mammalian target of rapamycin (mTOR), a key downstream molecule of insulin-phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, plays an important role in cardioprotection. However, the role of cardiac mTOR in ischemic injury in metabolic syndrome has not been well defined. To address this question, we studied the effect of overexpressing cardiac mTOR on cardiac function following ischemia/reperfusion (I/R) in mice with high-fat diet (HFD)-induced obesity. In this study, we used transgenic mice with cardiac-specific overexpression of mTOR (mTOR-Tg) as reported previously. mTOR-Tg and WT mice at 6 weeks old were fed HFD (60% fat by calories) ad libitum for 14 weeks. Control mTOR-Tg and WT mice were fed a normal chow diet (NCD). At 14 weeks after HFD, glucose and insulin tolerance tests demonstrated that HFD generated glucose intolerance and insulin resistance in both mTOR-Tg (n=20) and WT (n=24) mice. Body weight (BW) and heart weight (HW) were significantly higher in HFD mice than SCD mice (p<0.001 for BW in both strains; p<0.001 and p<0.01 for HW/tibia length, WT and mTOR-Tg, respectively) but there was no difference in BW or HW between HFD-mTOR-Tg and HFD-WT mice. Hearts from all four groups were subjected to global I/R (20 min ischemia, 40 min reperfusion) in the ex vivo Langendorff perfusion model. Baseline left ventricular developed pressure (LVDP) was higher in HFD mice than NCD mice in both strains [185.8 ± 10.7 vs. 143.6 ± 5.0 mmHg, HFD-WT (n=11) vs. NCD-WT (n=10) mice, p<0.01; 178.6 ± 10.1 vs. 135.0 ± 6.3, HFD-mTOR-Tg (n=8) vs. NCD-mTOR-Tg (n=11) mice, p<0.01]. Functional recovery after I/R was significantly lower in HFD-WT mice than NCD-WT mice (percent recovery of LVDP, 15.3 ± 5.4 vs. 44.6 ± 6.3 %, HFD-WT vs. NCD-WT mice, p<0.01). Intriguingly, there was no significant difference in LVDP recovery between HFD-mTOR-Tg and NCD-mTOR-Tg mice (36.5±10.8 vs. 58.8±6.0 %, HFD-mTOR-Tg vs. NCD-mTOR-Tg mice, n.s.). These findings suggest that cardiac mTOR is sufficient to substantially limit the metabolic syndrome-induced cardiac dysfunction following I/R in a mouse model of obesity with glucose intolerance and insulin resistance.

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Perivascular Adipose Tissue-Enhanced Vasodilation in Metabolic Syndrome Rats by Apelin and N-Acetyl–l-Cysteine-Sensitive Factor(s)

International Journal of Molecular Sciences ◽

10.3390/ijms20010106 ◽

2018 ◽

Vol 20 (1) ◽

pp. 106 ◽

Cited By ~ 2

Author(s):

Satomi Kagota ◽

Kana Maruyama-Fumoto ◽

Saki Iwata ◽

Miho Shimari ◽

Shiori Koyanagi ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Mrna Level ◽

Receptor Activation ◽

At1 Receptor ◽

Mesenteric Arteries ◽

Mrna Levels ◽

Perivascular Adipose Tissue ◽

Age Related ◽

Sensitive Factor

Perivascular adipose tissue (PVAT) can regulate vascular tone. In mesenteric arteries of SHRSP.Z-Leprfa/IzmDmcr rats (SHRSP.ZF) with metabolic syndrome, vascular dysfunction is compensated by PVAT-dependent mechanisms that disappear with increasing age. In this study, we investigated the mechanisms of the age-related changes and responsible factor(s) involved in the enhancing effects of mesenteric arterial PVAT in SHRSP.ZF. Acetylcholine- and sodium nitroprusside-induced relaxations of isolated arteries were greater with PVAT than without PVAT at 17 and 20 weeks of age (wks), and as expected, this enhancement by the presence of PVAT disappeared at 23 wks. PVAT mRNA levels of angiotensin II type 1 (AT1) receptor-associated protein was less and AT1 receptor was unchanged at 23 wks when compared to 20 wks. At 20 wks, the enhanced acetylcholine-induced relaxation by the presence of PVAT was inhibited by N-acetyl-l-cysteine (NAC). Acetylcholine-induced relaxation of arteries without PVAT was increased in the presence of exogenously added apelin. PVAT mRNA level of apelin was higher in SHRSP.ZF than in control Wistar-Kyoto rats, and the level was decreased with aging. These results suggest that AT1 receptor activation in PVAT, and changes in the regulation of apelin and a NAC-sensitive factor are related to the age-dependent deterioration of the vasodilation enhancing effects of mesenteric arterial PVAT in SHRSP.ZF.

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The prebiotic fiber inulin ameliorates cardiac, adipose tissue, and hepatic pathology but exacerbates hypertriglyceridemia in rats with metabolic syndrome

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00657.2020 ◽

2020 ◽

Author(s):

Yuki Komatsu ◽

Kiyoshi Aoyama ◽

Mamoru Yoneda ◽

Sao Ashikawa ◽

Shiho Nakano ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Dietary Fiber ◽

Metabolic Disorders ◽

Regulatory Element ◽

Left Ventricular ◽

Soluble Fiber ◽

High Fiber ◽

Obese Rats ◽

Hepatic Pathology

Prebiotics ameliorate dysbiosis and influence metabolism and the immune system, but their effects on cardiovascular complications in metabolic disorders remain largely unknown. We here investigated the effects of the soluble fiber inulin on cardiac, adipose tissue, and hepatic pathology as well as on metabolic disorders in DahlS.Z-Leprfa/Leprfa (DS/obese) rats, an animal model of metabolic syndrome (MetS). DS/obese rats and their homozygous lean (DahlS.Z-Lepr+/Lepr+, or DS/lean) littermate controls were fed a purified diet containing 5% or 20% inulin from 9 to 13 weeks of age. The high-fiber diet ameliorated hypertension, left ventricular inflammation, fibrosis, and diastolic dysfunction, attenuated adipose tissue inflammation and fibrosis as well as alleviated the elevation of interleukin-6 levels, without affecting insulin resistance, in DS/obese rats. In addition, high fiber intake ameliorated lipid accumulation, inflammation, and fibrosis, attenuated the reduction in AMPK activity and the up-regulation of sterol regulatory element binding protein-1c gene expression, and further increased the expression of microsomal triglyceride transfer protein gene, in the liver of DS/obese rats. It also mitigated increases in total and non-high-density lipoprotein-cholesterol levels but increased the triglyceride concentration in serum in these rats. None of these parameters was affected by high dietary fiber in DS/lean rats. The proportion of regulatory T cells in adipose tissue was influenced by dietary fiber but not by genotype. Our results indicate that inulin exacerbates hypertriglyceridemia but alleviates hypertension and cardiac injury as well as adipose tissue and hepatic pathology in MetS rats.

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