The effects of angiotensin receptor neprilysin inhibition by sacubitril/valsartan on adipose tissue transcriptome and protein expression in obese hypertensive patients (original) (raw)
Related papers
2006
To clarify the mechanism of the effects of angiotensin II AT 1 receptor antagonists on adipose tissue, we treated 8 week-old male Wistar Kyoto rats with the angiotensin II AT 1 receptor antagonist Candesartan cilexetil (10 mg/kg/day) for 18 weeks. Candesartan cilexetil reduced body weight gain, decreased fat tissue mass due to hypotrophy of epididymal and retroperitoneal adipose tissue and decreased adipocyte size without changing the number of adipocytes. Candesartan cilexetil decreased serum leptin levels and epididymal leptin mRNA, increased serum adiponectin levels and epididymal adiponectin mRNA, decreased epididymal tumor necrosis factor alpha (TNFα) mRNA, and increased fatty acid synthase mRNA. Considered free of peroxisome proliferator-activated receptor γ (PPARγ) agonist activity, Candesartan cilexetil increased epididymal expression of PPARγ mRNA. The effects of Candesartan cilexetil on adipokine production and release may be attributable to PPARγ activation and/or decrease in adipocyte cell size. In addition, Candesartan cilexetil treatment increased the expression of epididymal angiotensin II AT 2 receptor mRNA and protein and decreased the expression of renin receptor mRNA. These results suggest that Candesartan cilexetil influences lipid metabolism in adipose tissue by promoting adipose tissue rearrangement and modulating adipokine expression and release. These effects are probably consequences of local angiotensin II AT 1 receptor inhibition, angiotensin II AT 2 receptor stimulation, and perhaps additional angiotensin II-independent mechanisms. Our results indicate that the activity of local renin-angiotensin system plays an important role in adipose tissue metabolism. The decrease in the pro-inflammatory cytokine TNFα and the increase in the anti-inflammatory adipokine adiponectin indicate that Candesartan cilexetil may exert significant anti-inflammatory properties.
General Physiology and Biophysics
Angiotensin II exerts its action via at least two distinct receptor subtypes designated AT1 and AT2. AT1 receptors seem to be responsible for most of the known angiotensin II effects while the role of AT2 receptors is not yet clear. Adipocytes of adult rats express exclusively the AT1 subtype. Angiotensin II stimulates prostacyclin release in adult rat adipocytes and in mouse preadipocytes. In the latter prostacyclin release is completely blocked by an AT2 receptor antagonist. Adipocyte angiotensin II receptors seem to be regulated by age and fat mass. Blockade of these receptors by an AT1 antagonist seems to prevent adipose tissue hypertrophy. Moreover, adipose tissue contains all the main components of the renin-angiotensin system such as angiotensinogen, angiotensin converting enzyme, angiotensin II and angiotensin II receptors. Angiotensinogen expression in adipocytes is stimulated by a high fat diet concurrent with enlargement of fat mass, associated with insulin resistance. An...
Critical Reviews in Biochemistry and Molecular Biology, 2012
The renin-angiotensin system (RAS) is classically known for its role in regulation of blood pressure, fluid and electrolyte balance. In this system, angiotensinogen (Agt), the obligate precursor of all bioactive angiotensin peptides, undergoes two enzymatic cleavages by renin and angiotensin converting enzyme (ACE) to produce angiotensin I (Ang I) and angiotensin II (Ang II), respectively. The contemporary view of RAS has become more complex with the discovery of additional angiotensin degradation pathways such as ACE2. All components of the RAS are expressed in and have independent regulation of adipose tissue. This local adipose RAS exerts important auto/paracrine functions in modulating lipogenesis, lipolysis, adipogenesis as well as systemic and adipose tissue inflammation. Mice with adipose-specific Agt overproduction have a 30% increase in plasma Agt levels and develop hypertension and insulin resistance, while mice with adipose-specific Agt knockout have a 25% reduction in Agt plasma levels, demonstrating endocrine actions of adipose RAS. Emerging evidence also points towards a role of RAS in regulation of energy balance. Because adipose RAS is overactivated in many obesity conditions, it is considered a potential candidate linking obesity to hypertension, insulin resistance and other metabolic derangements.
Angiotensin II stimulates and atrial natriuretic peptide inhibits human visceral adipocyte growth
2008
Objective: Cardiovascular peptides such as angiotensin II (Ang II) and atrial natriuretic peptide (ANP) have metabolic effects on adipose cells. These peptides might also regulate adipocyte proliferation and visceral adipose tissue (VAT) expansion. Welldifferentiated and stabilized primary cultures of human visceral mature adipocytes (MA) and in vitro-differentiated preadipocytes (DPA) were used as a model to study regulation of VAT expansion. Methods: Adipocyte differentiation was evaluated by Oil Red O staining and antiperilipin antibodies. MA and DPA from intraand retro-peritoneal depots were treated with increasing Ang II (with or without valsartan, a highly selective, competitive, 'surmountable' AT1 antagonist devoid of peroxisome proliferator-activated receptor g agonistic activity) or ANP concentrations. Cell counts and bromodeoxyuridine incorporation were used to evaluate proliferation. Apoptosis was evaluated by Hoechst 33342 staining. 8-Bromo cyclic guanosine monophosphate (8Br-cGMP) was used to investigate ANP effects, and real-time PCR to evaluate Ang II and ANP receptors' expression. Results: Cell proliferation was progressively stimulated by increasing Ang II concentrations (starting at 10À11 M) and inhibited by ANP (already at 10À13 M) in both MA and DPA. Co-incubation with increasing Ang II concentrations and valsartan indicated that Ang II effects were AT1-mediated. Indeed, AT2 receptors were not expressed. Valsartan alone slightly inhibited basal proliferation indicating an autocrine/paracrine growth factor-like effect of endogenous, adipocyte-derived Ang II. 8Br-cGMP experiments indicated that the effects of ANP were mediated by the guanylyl cyclase type A receptor.
Angiotensin II: a hormone that affects lipid metabolism in adipose tissue
Background: Alterations in adipose tissue lipolysis may contribute to the pathophysiology of obesity and insulin resistance. We examined the effects of angiotensin II (Ang II) on abdominal subcutaneous adipose tissue lipolysis in humans. Methods and results: First, adipocytes obtained from nine normal weight and seven obese subjects were stimulated with Ang II (10 À14 -10 À6 M). Glycerol concentration in the medium, used as an indicator of adipocyte lipolysis, was significantly reduced (B20%) after Ang II stimulation in adipocytes from normal weight (P ¼ 0.04) and obese subjects (Po0.001). Based on these observations, adipocytes of seven additional obese subjects were stimulated with lower doses of Ang II (10 À17 -10 À6 M) in the presence and absence of Ang II type 1 (AT 1 ) receptor blockade. Lipolysis was dose dependently inhibited by B20 to 25% after Ang II stimulation (P ¼ 0.001). AT 1 receptor blockade completely abolished the Ang II-induced effects (P ¼ 0.35). Conclusion: Ang II directly inhibits abdominal subcutaneous adipocyte lipolysis in normal weight and obese subjects via the AT 1 receptor.
Journal of the American Heart Association, 2013
Metabolic disorders with visceral obesity have become a major medical problem associated with the development of hypertension, type 2 diabetes, and dyslipidemia and, ultimately, life-threatening cardiovascular and renal diseases. Adipose tissue dysfunction has been proposed as the cause of visceral obesity-related metabolic disorders, moving the tissue toward a proinflammatory phenotype. Here we first report that adipose tissues from patients and mice with metabolic disorders exhibit decreased expression of ATRAP/Agtrap, which is a specific binding modulator of the angiotensin II type 1 receptor, despite its abundant expression in adipose tissues from normal human and control mice. Subsequently, to examine a functional role of ATRAP in the pathophysiology of metabolic disorders, we produced homozygous ATRAP deficient (Agtrap(-/-)) mice, which exhibited largely normal physiological phenotype at baseline. Under dietary high fat loading, Agtrap(-/-) mice displayed systemic metabolic dy...
Insulinotropic Effects of Neprilysin and/or Angiotensin Receptor Inhibition in Mice
Frontiers in Endocrinology
Treatment of heart failure with the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan improved glycemic control in individuals with type 2 diabetes. The relative contribution of neprilysin inhibition versus angiotensin II receptor antagonism to this glycemic benefit remains unknown. Thus, we sought to determine the relative effects of the neprilysin inhibitor sacubitril versus the angiotensin II receptor blocker valsartan on beta-cell function and glucose homeostasis in a mouse model of reduced first-phase insulin secretion, and whether any beneficial effects are additive/synergistic when combined in sacubitril/valsartan. High fat-fed C57BL/6J mice treated with low-dose streptozotocin (or vehicle) were followed for eight weeks on high fat diet alone or supplemented with sacubitril, valsartan or sacubitril/valsartan. Body weight and fed glucose levels were assessed weekly. At the end of the treatment period, insulin release in response to intravenous glucose, insulin sen...
Therapeutic advances in cardiovascular disease, 2015
Whether angiotensin II receptor blockade improves skeletal muscle fatty acid oxidation in overweight and obese humans is unknown. The purpose of the study was to test the hypothesis that the angiotensin II receptor blocker, olmesartan, would increase fatty acid oxidation and the activity of enzymes associated with oxidative metabolism in skeletal muscle of overweight and obese humans. A total of 12 individuals (6 men and 6 women) aged 18-75 and with a body mass index ⩾25 kg/m(2) were assigned to olmesartan or placebo for 8 weeks in a crossover fashion. Fatty acid oxidation was measured before and after each intervention by counting the (14)CO2 produced from [1-(14)C] palmitic acid in skeletal muscle homogenates. Fatty acid oxidation was not significantly different between treatment periods at baseline and post intervention. In addition, the enzyme activities of citrate synthase and β-hydroxyacyl-coenzyme A dehydrogenase in skeletal muscle homogenates did not differ between treatment...