Gastric mucosal devitalization improves blood pressure, renin and cardiovascular lipid deposition in a rat model of obesity

Andreas Oberbach, Nadine Schlichting, Yvonne Kullnick, Marco Heinrich, Stefanie Lehmann, Ulf Retschlag, Maik Friedrich, Lea Fayad, Arne Dietrich, Mouen A Khashab, Anthony N Kalloo, Vivek Kumbhari, Andreas Oberbach, Nadine Schlichting, Yvonne Kullnick, Marco Heinrich, Stefanie Lehmann, Ulf Retschlag, Maik Friedrich, Lea Fayad, Arne Dietrich, Mouen A Khashab, Anthony N Kalloo, Vivek Kumbhari

Abstract

Background and study aims In lieu of the drawbacks of metabolic surgery, a method of mimicking resection of the gastric mucosa could be of value to those with obesity-related cardiovascular disease (CVD). Our study aims to investigate the effect of gastric mucosal devitalization (GMD) on blood pressure (BP) and cardiovascular lipid deposition in a rat model of obesity. Methods GMD of 70 % of the stomach was achieved by argon plasma coagulation. GMD was compared to sleeve gastrectomy (SG) and sham (SH) in a high-fat-diet-induced rat model of obesity (48 rats). At 8 weeks, we measured noninvasive BP, renin, vessel relaxation and ghrelin receptor regulation in the aorta. In addition, we quantified cardiac lipid deposition and lipid droplet deposition in cardiac muscle and aorta. Results GMD and SG were observed to have similar reductions in body weight, visceral adiposity, and serum lipid profile compared to SH rats. GMD resulted in a significant reduction in arterial BP compared to SH. Furthermore, there were significant reductions in plasma renin activity and percentage of phenylnephrine constriction to acetylcholine at the aortic ring in GMD rats compared to SH, providing insights into the mechanisms behind the reduced BP. Interestingly, the reduced BP occurred despite a reduction in endothelial ghrelin recteptor activation. Cardiac lipid content was significantly reduced in GMD rats. Lipid deposition, as illustrated by Nile Red stain, was reduced in cardiac muscle and the aorta. Conclusion GMD resulted in a significant improvement in BP, renin and cardiovascular lipid deposition. GMD deserves further attention as a method of treating obesity-related CVD.

Conflict of interest statement

Competing interests Dr. Kumbhari is a consultant for Apollo Endosurgery, Medtronic, ReShape Lifesciences, Boston Scientific and Pentax. He has also received research support from Apollo Endosurgery and ERBE. Mouen A. Khashab is on the medical advisory board for Boston Scientific and Olympus America and is a consultant for Boston Scientific, Olympus America, and Medtronic. Anthony N Kalloo is a founding member, equity holder, and consultant for Apollo Endosurgery.

Figures

Fig. 1
Fig. 1
Regulation of blood pressure and renin activity in the study population. Measurements in the animal groups at 15 weeks of age (11 weeks of HFD) and 23 weeks of age (8 weeks after intervention).aNoninvasive measurement of blood pressure using a tail cuff setup revealed an increased systolic and diastolic blood pressure in rats after 11 weeks of feeding HFD compared to CD rats. Eight weeks after intervention, GMD treated rats showed significant reduction of both pressure values compared to SH.bPlasma renin activity was not altered after receiving 11 weeks HFD. Eight weeks after intervention, renin activity was significantly reduced in GMD and SG rats. CD, chow diet; HFD, high-fat diet; GMD, gastric mucosal devitalization; SG, sleeve gastrectomy; SH, sham operation
Fig. 2
Fig. 2
Ex vivo study of response of the aorta in rats after concentration-dependent stimulation. Measurements in the animal groups at 15 weeks of age (11 weeks of HFD) and 23 weeks of age (8 weeks after intervention).aAortic rings were stimulated with 80 mM KCl to visualize their maximal contraction (mean ± SEM).bPhenylepinephrine (PE)-dependent contraction is plotted relative to the baseline of each group. The stimulation was finished when contraction reaches > 70 % of KCl-contraction.cAcetylcholine (Ach)-dependent relaxation is plotted relative to the respective maximal PE-contraction (100 nM). Insets are calculated area under the curve (AUC; mean±SEM) and represent the change in contraction depending on the concentration of the relative stimulus Ach. Statistical tests used were thet-test and one-way ANOVA with a post-hoc Tukey’s – Kramer test andP < 0.05. CD, chow diet; HFD, high-fat diet; GMD, gastric mucosal devitalization; SG, sleeve gastrectomy; SH, sham operation
Fig. 3
Fig. 3
Endothelial ghrelin receptor expression in rat aorta.aHE-stain illustrates the structural characteristics of the rat aorta: 1 – Blood vessel lumen, 2 – Endothelium, 3 – Aortic smooth muscle cells, 4 – Visceral fat tissue, blue – cell nuclei.bFluorescence images of paraffin slices show Ghrelin-receptor localization (GHSR) (green) on aortic endothelium of each respective group. Nuclei – Dapi (blue), inset represents stain control without primary antibody. (C + D) Quantitative analysis of GHSR using Western Blot. GSHR, growth hormone secretagogue receptor 1a; CD, chow diet; HFD, high-fat diet; GMD, gastric mucosal devitalization; SG, sleeve gastrectomy; SH, sham operation; GAPDH, glyceraldehyde 3-phosphate dehydrogenase.
Fig. 4
Fig. 4
Regulation of lipid content and lipid droplet-associated proteins perilipin 1 and perilipin 2 in cardiac muscle. Measurements in the animal groups at 15 weeks of age (11 weeks of HFD) and 23 weeks of age (8 weeks after intervention). Values are means + SD of dietary groups (CD, chow diet; HFD, high-fat diet) and intervention groups (GMD, gastric mucosa devitalization; SG, sleeve gastrectomy; SH, sham surgery). Significant differences (P < .05) between GMD and SG compared with SH are indicated by asterisks.aCardiac lipid content in the respective intervention groups. Note, GMD rats had significantly reduced cardiac lipid content at 8 weeks compared to SH.bHE-stain illustrates the structural characteristics of cardiac muscle.cImmunofluorescence of cryo-slices illustrate lipid droplet concentration and size (Nile red stain) as well as expression of lipid droplet associated proteins PLIN1 and PLIN2 after 8 weeks of intervention (green).d,eLipid droplet associated proteins were quantified by Western Blot. CD, chow diet; HFD, high-fat diet; GMD, gastric mucosal devitalization; SG, sleeve gastrectomy; SH, sham operation; PLIN1, perilipin 1; PLIN2 – perilipin 2.
Fig. 5
Fig. 5
Nile Red stain of cardiac muscle and aorta.aFluorescence staining with Nile Red illustrating cardiac muscle lipid content.bFluorescence staining with Nile Red illustrating aortic wall lipid content. CD, chow diet; HFD, high-fat diet; GMD, gastric mucosal devitalization; SG, sleeve gastrectomy; SH, sham operation.

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