Metabolic Syndrome Abolishes Glucagon-Like Peptide 1 Receptor Agonist Stimulation of SERCA in Coronary Smooth Muscle

Dineen, Stacey L.; McKenney, Mikaela; Bell, Lauren N.; Fullenkamp, Allison M.; Schultz, Kyle A.; Alloosh, Mouhamad; Chalasani, Naga; Sturek, Michael

doi:10.2337/db14-1790

Cited by 17 publications

(13 citation statements)

References 20 publications

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“…However, we observed an increase in R A , which was largely explained by the increase in MAP and, as such, may reflect a (conserved) autoregulatory response activated by stretching of the vascular smooth muscle cells. Although such causality cannot definitely be determined in this study, our findings are compatible with previous studies demonstrating impaired NO-dependent vasodilation in type 2 diabetes patients [ 31 ] and vascular resistance to GLP-1RA in swine with metabolic syndrome [ 32 ]. Increases in BP following acute GLP-1RA-administration have been widely observed, and both direct sympathetic nervous system activation and reflex tachycardia as a response to vasodilation have been implicated, although the exact mechanism is unclear [ 33 ].…”

Section: Discussionsupporting

confidence: 92%

Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial

et al. 2016

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Aims/hypothesisThis study aimed to investigate the acute renal effects of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide in type 2 diabetes patients.MethodsWe included overweight (BMI 25–40 kg/m2) men and postmenopausal women, aged 35–75 years with type 2 diabetes (HbA1c 48–75 mmol/mol; 6.5–9.0%) and estimated GFR ≥ 60 ml min−1 1.73 m−2. Exenatide or placebo (NaCl solution, 154 mmol/l) was administrated intravenously in an acute, randomised, double-blind, placebo-controlled trial conducted at the Diabetes Center VU University Medical Center (VUMC). GFR (primary endpoint) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance, respectively, based on timed urine sampling. Filtration fraction (FF) and effective renal vascular resistance (ERVR) were calculated, and glomerular hydrostatic pressure (PGLO) and vascular resistance of the afferent (RA) and efferent (RE) renal arteriole were estimated. Tubular function was assessed by absolute and fractional excretion of sodium (FENa), potassium (FEK) and urea (FEU), in addition to urine osmolality, pH and free water clearance. Renal damage markers, BP and plasma glucose were also determined.ResultsOf the 57 patients randomised by computer, 52 were included in the final analyses. Exenatide (n = 24) did not affect GFR (mean difference +2 ± 3 ml min−1 1.73 m−2, p = 0.489), ERPF, FF, ERVR or PGLO, compared with placebo (n = 28). Exenatide increased RA (p < 0.05), but did not change RE. Exenatide increased FENa, FEK, urine osmolality and pH, while FEU, urinary flow and free water clearance were decreased (all p < 0.05). Osmolar clearance and renal damage makers were not affected. Diastolic BP and mean arterial pressure increased by 3 ± 1 and 6 ± 2 mmHg, respectively, whereas plasma glucose decreased by 1.4 ± 0.1 mmol/l (all p < 0.05).Conclusions/interpretationExenatide infusion does not acutely affect renal haemodynamics in overweight type 2 diabetes patients at normal filtration levels. Furthermore, acute GLP-1RA administration increases proximal sodium excretion in these patients.Trial registrationClincialTrials.gov NCT01744236FundingThe research leading to these results has been funded from: (1) the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 282521 – the SAFEGUARD project; and (2) the Dutch Kidney Foundation, under grant agreement IP12.87.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3938-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Section: Discussionsupporting

confidence: 92%

Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial

et al. 2016

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“…In addition, isoforms of SERCA in lymphatic endothelial cells and its distinct roles in the modulation of flow-mediated Ca 2+ release in MetSyn needs to be investigated 34 . www.nature.com/scientificreports/ Increasing SERCA expression or activity has been shown to provide protective effects on cardiac muscle and vascular smooth muscle cells in several metabolic diseases 26,29,54,55 . A small molecule, CDN1163, activates SERCA by allosteric mechanism and improves Ca 2+ homeostasis both in vivo and in vitro [35][36][37] .…”

Section: Discussionmentioning

confidence: 99%

“…Disrupting ER Ca 2+ in isolated bovine lymphatic vessels caused lymphatic dysfunction 25 . Additionally, SERCA2 activity and expression are diminished in vascular smooth muscle 26,27 and heart 28,29 in different animal models of obesity/ diabetes, highlighting a potential pathological role for SERCA2 dysfunction and disturbed intracellular Ca 2+ homeostasis in the development of metabolic abnormalities in insulin resistance and diabetes. However, the role of SERCA2 in lymphatic pumping activity and possible pathophysiological roles in MetSyn have not yet been examined.…”

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confidence: 99%

Roles of sarcoplasmic reticulum Ca2+ ATPase pump in the impairments of lymphatic contractile activity in a metabolic syndrome rat model

Lee

Chakraborty

Muthuchamy

2020

Sci Rep

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the intrinsic lymphatic contractile activity is necessary for proper lymph transport. Mesenteric lymphatic vessels from high-fructose diet-induced metabolic syndrome (MetSyn) rats exhibited impairments in its intrinsic phasic contractile activity; however, the molecular mechanisms responsible for the weaker lymphatic pumping activity in MetSyn conditions are unknown. Several metabolic disease models have shown that dysregulation of sarcoplasmic reticulum ca 2+ Atpase (SeRcA) pump is one of the key determinants of the phenotypes seen in various muscle tissues. Hence, we hypothesized that a decrease in SeRcA pump expression and/or activity in lymphatic muscle influences the diminished lymphatic vessel contractions in MetSyn animals. Results demonstrated that SERCA inhibitor, thapsigargin, significantly reduced lymphatic phasic contractile frequency and amplitude in control vessels, whereas, the reduced MetSyn lymphatic contractile activity was not further diminished by thapsigargin. While SERCA2a expression was significantly decreased in MetSyn lymphatic vessels, myosin light chain 20, MLC 20 phosphorylation was increased in these vessels. Additionally, insulin resistant lymphatic muscle cells exhibited elevated intracellular calcium and decreased SERCA2a expression and activity. The SERCA activator, CDN 1163 partially restored lymphatic contractile activity in MetSyn lymphatic vessel by increasing phasic contractile frequency. Thus, our data provide the first evidence that SERCA2a modulates the lymphatic pumping activity by regulating phasic contractile amplitude and frequency, but not the lymphatic tone. Diminished lymphatic contractile activity in the vessels from the MetSyn animal is associated with the decreased SERCA2a expression and impaired SERCA2 activity in lymphatic muscle.

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“…histidine-rich calcium binding protein). GLP-1 mimetics have been found to differently modulate calcium handling in vascular smooth muscle of swine depending on obesity [18], but, until now, have not been associated with direct changes in the level of calcium handling proteins in myocardium. Modulation of calcium handling and titin protein abundance has profound implications for signaling (whether by calcium as a second messenger, or titin hypertrophic signaling e.g.…”

Section: Discussionmentioning

confidence: 99%

Obesity alters molecular and functional cardiac responses to ischemia/reperfusion and glucagon-like peptide-1 receptor agonism

et al. 2016

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This study tested the hypothesis that obesity alters the cardiac response to ischemia/reperfusion and/or glucagon like peptide-1 (GLP-1) receptor activation, and that these differences are associated with alterations in the obese cardiac proteome and microRNA (miR) transcriptome. Ossabaw swine were fed normal chow or obesogenic diet for 6 months. Cardiac function was assessed at baseline, during a 30-min coronary occlusion, and during 2 hours of reperfusion in anesthetized swine treated with saline or exendin-4 for 24 hours. Cardiac biopsies were obtained from normal and ischemia/reperfusion territories. Fat-fed animals were heavier, and exhibited hyperinsulinemia, hyperglycemia, and hypertriglyceridemia. Plasma troponin-I concentration (index of myocardial injury) was increased following ischemia/reperfusion and decreased by exendin-4 treatment in both groups. Ischemia/reperfusion produced reductions in systolic pressure and stroke volume in lean swine. These indices were higher in obese hearts at baseline and relatively maintained throughout ischemia/reperfusion. Exendin-4 administration increased systolic pressure in lean swine but did not affect blood pressure in obese swine. End-diastolic volume was reduced by exendin-4 following ischemia/reperfusion in obese swine. These divergent physiologic responses were associated with obesity-related differences in proteins related to myocardial structure/function (e.g. titin) and calcium handling (e.g. SERCA2a, histidine-rich Ca2+ binding protein). Alterations in expression of cardiac miRs in obese hearts included miR-15, miR-27, miR-130, miR-181, and let-7. Taken together, these observations validate this discovery approach and reveal novel associations that suggest previously undiscovered mechanisms contributing to the effects of obesity on the heart and contributing to the actions of GLP-1 following ischemia/reperfusion.

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Metabolic Syndrome Abolishes Glucagon-Like Peptide 1 Receptor Agonist Stimulation of SERCA in Coronary Smooth Muscle

Cited by 17 publications

References 20 publications

Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial

Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial

Roles of sarcoplasmic reticulum Ca2+ ATPase pump in the impairments of lymphatic contractile activity in a metabolic syndrome rat model

Obesity alters molecular and functional cardiac responses to ischemia/reperfusion and glucagon-like peptide-1 receptor agonism

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