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

2020 ◽  
Author(s):  
Yang Lee ◽  
Sanjukta Chakraborty ◽  
Mariappan Muthuchamy
Keyword(s):  
Metabolic Syndrome ◽  
Sarcoplasmic Reticulum ◽  
Molecular Mechanisms ◽  
Contractile Activity ◽  
Lymphatic Vessels ◽  
Insulin Resistant ◽  
High Fructose ◽  
Serca Pump ◽  
Lymphatic Pumping ◽  
Pumping Activity

AbstractThe 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 Ca2+ 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, MLC20 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 increased phasic contractile frequency in the vessels from MetSyn, thereby, partially restored lymph flow. 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.

Decreased lymphatic pumping after intravenous endotoxin administration in sheep

1987 ◽  
Vol 253 (6) ◽  
pp. H1349-H1357 ◽  
Author(s):  
R. M. Elias ◽  
M. G. Johnston ◽  
A. Hayashi ◽  
W. Nelson
Keyword(s):  
Contractile Activity ◽  
Lymphatic Vessels ◽  
Transmural Pressure ◽  
Sheep Model ◽  
Endotoxin Administration ◽  
Maximum Inhibition ◽  
Spontaneous Contractions ◽  
Lymphatic Pumping ◽  
Pumping Activity

The effects of endotoxin on the ability of lymphatic vessels to pump fluid in vivo have been assessed with the use of a sheep model system that permits analysis of lymph pumping in sheep without the complication of variable lymph inputs. This involved the isolation of intestinal lymphatic vessels from all lymph input, with saline or lymph provided from a reservoir. The blood and nerve supplies to the vessel were left intact. With no net driving pressure, but with a transmural pressure applied to the vessel to initiate spontaneous contractions and fluid pumping, the intravenous administration of endotoxin (3.3 micrograms/kg in anesthetized sheep and 33 micrograms/kg in nonanesthetized animals) reduced fluid propulsion in both groups of animals (P less than 0.02 and P less than 0.03, respectively). Comparisons with animals that did not receive endotoxin revealed maximum inhibition greater than 90% in anesthetized and 50% in nonanesthetized sheep. Normal pulsatile lymphatic pressures (produced from lymphatic contractions) were reduced in frequency and amplitude after endotoxin administration. Endotoxin itself had no effect on the vessels when added to the fluid in the reservoir, suggesting that the inhibition of the "lymph pump" was mediated through the interaction of endotoxin with cellular or humoral elements in the host. In addition to suppression of lymphatic contractile activity, the intravenous injection of endotoxin enhanced lymph formation as indicated by the 3- to 10-fold increases in lymph flow rates in the two groups. We conclude that, for a given transmural pressure, the systemic administration of endotoxin reduces lymphatic pumping activity. We speculate that this effect may be important in the pathogenesis of the edema associated with sepsis.

scholarly journals Impairments in the intrinsic contractility of mesenteric collecting lymphatics in a rat model of metabolic syndrome

2012 ◽  
Vol 302 (3) ◽  
pp. H643-H653 ◽  
Author(s):  
Scott D. Zawieja ◽  
Wei Wang ◽  
Xin Wu ◽  
Zhanna V. Nepiyushchikh ◽  
David C. Zawieja ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Serum Insulin ◽  
Lymphatic Vessels ◽  
Lymphatic Function ◽  
Cell Coverage ◽  
High Fructose ◽  
Contractile Parameters ◽  
Generating Capacity ◽  
Chronotropic Effects ◽  
Lymphatic Pumping

Numerous studies on metabolic syndrome (MetSyn), a cluster of metabolic abnormalities, have demonstrated its profound impact on cardiovascular and blood microvascular health; however, the effects of MetSyn on lymphatic function are not well understood. We hypothesized that MetSyn would modulate lymphatic muscle activity and alter muscularized lymphatic function similar to the impairment of blood vessel function associated with MetSyn, particularly given the direct proximity of the lymphatics to the chronically inflamed adipose depots. To test this hypothesis, rats were placed on a high-fructose diet (60%) for 7 wk, and their progression to MetSyn was assessed through serum insulin and triglyceride levels in addition to the expression of metabolic and inflammatory genes in the liver. Mesenteric lymphatic vessels were isolated and subjected to different transmural pressures while lymphatic pumping and contractile parameters were evaluated. Lymphatics from MetSyn rats had significant negative chronotropic effects at all pressures that effectively reduced the intrinsic flow-generating capacity of these vessels by ∼50%. Furthermore, lymphatics were remodeled to a significantly smaller diameter in the animals with MetSyn. Wire myograph experiments demonstrated that permeabilized lymphatics from the MetSyn group exhibited a significant decrease in force generation and were less sensitive to Ca2+, although there were no significant changes in lymphatic muscle cell coverage or morphology. Thus, our data provide the first evidence that MetSyn induces a remodeling of collecting lymphatics, thereby effectively reducing their potential load capabilities and impairing the intrinsic contractility required for proper lymph flow.

Modulation of lymphatic pumping by lymph-borne factors after endotoxin administration in sheep

1990 ◽  
Vol 68 (1) ◽  
pp. 199-208 ◽  
Author(s):  
R. M. Elias ◽  
M. G. Johnston
Keyword(s):  
Potent Inhibitor ◽  
Lymphatic Vessels ◽  
Transmural Pressure ◽  
Test Animal ◽  
Indwelling Catheter ◽  
Endotoxin Administration ◽  
Lymphatic Pumping ◽  
Pumping Activity

The purpose of this study was to test the hypothesis that endotoxin administration to sheep results in host-derived lymph-borne factors that modulate lymphatic pumping activity. To achieve this, two sheep were used for each experiment. In the test animal, a segment of intestinal lymphatic was isolated from all lymph input and provided with lymph from a reservoir. Pumping activity was initiated with a fixed transmural pressure applied to the test vessel, and the only input to this duct was provided by lymph from an indwelling catheter in a second donor sheep. The intravenous administration of endotoxin to the donor animals (33 micrograms/kg) generally resulted in increased pumping in the test vessels over the 1st h, but this was followed by reductions in pumping until flow stopped in all preparations. In control experiments (no endotoxin administered) pumping was unaffected. Further investigation revealed that these activities were relatively unstable and, in the case of the inhibitory material, appeared to act by decreasing the sensitivity of the vessel to changes in transmural pressure, because flow could be reestablished in the test vessels by elevating transmural pressures above the level originally chosen for the experiment. Endotoxin itself had no direct effect on sheep lymphatics in vivo or on bovine lymphatic vessels in vitro. However, the appearance of erythrocyte hemolysate (erythrolysate) in lymph was regularly observed after endotoxin infusion, and we demonstrated that erythrolysate (diluted to contain 10(-5) M hemoglobin) was a potent inhibitor of lymphatic pumping in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Involvement of the NO-cGMP-KATP channel pathway in the mesenteric lymphatic pump dysfunction observed in the guinea pig model of TNBS-induced ileitis

2013 ◽  
Vol 304 (6) ◽  
pp. G623-G634 ◽  
Author(s):  
Ryan Mathias ◽  
Pierre-Yves von der Weid
Keyword(s):  
Guinea Pig ◽  
Intestinal Inflammation ◽  
Contractile Activity ◽  
Lymphatic Vessels ◽  
Pig Model ◽  
Trinitrobenzenesulfonic Acid ◽  
Potential Measurement ◽  
Inos Inhibitor ◽  
Guinea Pig Model ◽  
Lymphatic Pumping

Mesenteric lymphatic vessels actively transport lymph, immune cells, fat, and other macromolecules from the intestine via a rhythmical contraction-relaxation process called lymphatic pumping. We have previously demonstrated that mesenteric lymphatic pumping was compromised in the guinea pig model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced ileitis, corroborating clinical and experimental observations of a dilated and/or obstructed phenotype of these vessels in inflammatory bowel disease. Many mediators released during the inflammatory process have been shown to alter lymphatic contractile activity. Among them, nitric oxide (NO), an inflammatory mediator abundantly released during intestinal inflammation, decreases the frequency of lymphatic contractions through activation of ATP-sensitive potassium (KATP) channels. The objective of this study was to investigate the role of NO and KATP channels in the lymphatic dysfunction observed in the guinea pig model of TNBS-induced ileitis. Using quantitative real-time PCR, we demonstrated that expression of Kir6.1, SUR2B, and inducible NO synthase (iNOS) mRNAs was significantly upregulated in TNBS-treated animals. Pharmacological studies performed on isolated, luminally perfused mesenteric lymphatic vessels showed that the KATP channels blocker glibenclamide, the selective iNOS inhibitor 1400W, and the guanylyl cyclase inhibitor ODQ (1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one) significantly improved lymphatic pumping in quiescent lymphatic vessels from TNBS-treated animals. Membrane potential measurement with intracellular microelectrodes revealed that vessels from TNBS-treated animals were hyperpolarized compared with their sham counterpart and that the hyperpolarization was significantly attenuated in the presence of glibenclamide and ODQ. Our findings suggest that NO and KATP play a major role in the lymphatic contractile dysfunction that occurred as a consequence of the intestinal inflammation caused by TNBS.

scholarly journals Recent Developments in Rodent Models of High-Fructose Diet-Induced Metabolic Syndrome: A Systematic Review

Nutrients ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 2497
Author(s):  
Alvin Man Lung Chan ◽  
Angela Min Hwei Ng ◽  
Mohd Heikal Mohd Yunus ◽  
Ruszymah Bt Hj Idrus ◽  
Jia Xian Law ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Animal Studies ◽  
18Th Century ◽  
Disease Model ◽  
Hepatic Function ◽  
Chronic Illnesses ◽  
Paradigm Shifts ◽  
Response Factors ◽  
High Fructose ◽  
Recent Developments

Metabolic syndrome (MetS) is the physiological clustering of hypertension, hyperglycemia, hyperinsulinemia, dyslipidemia, and insulin resistance. The MetS-related chronic illnesses encompass obesity, the cardiovascular system, renal operation, hepatic function, oncology, and mortality. To perform pre-clinical research, it is imperative that these symptoms be successfully induced and optimized in lower taxonomy. Therefore, novel and future applications for a disease model, if proven valid, can be extrapolated to humans. MetS model establishment is evaluated based on the significance of selected test parameters, paradigm shifts from new discoveries, and the accessibility of the latest technology or advanced methodologies. Ultimately, the outcome of animal studies should be advantageous for human clinical trials and solidify their position in advanced medicine for clinicians to treat and adapt to serious or specific medical situations. Rodents (Rattus norvegicus and Mus musculus) have been ideal models for mammalian studies since the 18th century and have been mapped extensively. This review compiles and compares studies published in the past five years between the multitude of rodent comparative models. The response factors, niche parameters, and replicability of diet protocols are also compiled and analyzed to offer insight into MetS-related disease-specific modelling.

Kaempferol ameliorates symptoms of metabolic syndrome by improving blood lipid profile and glucose tolerance

2021 ◽  
Author(s):  
Ayasa Ochiai ◽  
Mahmoud Ben Othman ◽  
Kazuichi Sakamoto
Keyword(s):  
Metabolic Syndrome ◽  
Glucose Tolerance ◽  
Molecular Mechanisms ◽  
Ldl Receptor ◽  
Blood Lipid ◽  
Apolipoprotein A1 ◽  
High Density Lipoproteins ◽  
Blood Lipid Profile ◽  
Beneficial Effects ◽  
Apoa1 Gene

Abstract Kaempferol (KPF) is a dietary polyphenol reported to have various beneficial effects on human health. However, its molecular mechanisms in regulating lipid and glucose metabolism are not fully understood. This study examined the effects of KPF on obesity, dyslipidemia, and diabetes in Tsumura, Suzuki, Obese Diabetes (TSOD) mice. The six-week administration of KPF decreased fat weight, serum total cholesterol, and low-density lipoproteins (LDLs); increased high-density lipoproteins (HDLs); and improved glucose tolerance. Additionally, KPF increased LDL receptor (LDLR) and apolipoprotein A1 (ApoA1) gene expression and decreased serum resistin levels. These findings suggest that the decrease in LDL and the increase in HDL caused by KPF may be due to increases in hepatic LDLR and ApoA1 expression, respectively. Furthermore, it is possible that the improvement in glucose tolerance by KPF may occur via resistin reduction. These mechanisms may be parts of complex mechanism by which KPF improves metabolic syndrome.

scholarly journals Female offspring born to obese and insulin-resistant dams are not at increased risk for obesity and metabolic dysfunction during early development

2018 ◽  
Vol 96 (1) ◽  
pp. 97-102 ◽  
Author(s):  
Hanin Aburasayn ◽  
Rami Al Batran ◽  
Keshav Gopal ◽  
Malak Almutairi ◽  
Amina Eshreif ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Female Offspring ◽  
Metabolic Dysfunction ◽  
Insulin Resistant ◽  
The Metabolic Syndrome ◽  
Rate Versus ◽  
Increased Risk ◽  
Study Completion ◽  
Reduced Rate

The percentage of women who are obese at the time of conception or during pregnancy is increasing, with animal and human studies demonstrating that offspring born to obese dams or mothers are at increased risk for obesity and the metabolic syndrome. Our goal was to confirm in an experimental model of metabolic syndrome in the dam, whether the offspring would be at increased risk of obesity. Conversely, we observed that male offspring born to dams with metabolic syndrome had no alterations in their body mass profiles, whereas female offspring born to dams with metabolic syndrome were heavier at weaning, but exhibited no perturbations in energy metabolism. Moreover, they gained weight at a reduced rate versus female offspring born to healthy dams, and thus weighed less at study completion. Hence, our findings suggest that factors other than increased adiposity and insulin resistance during pregnancy are responsible for the increased risk of obesity in children born to obese mothers.

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