Abstract P199: Mas Receptor Deficiency Regulates Obesity-Hypertension and Cardiac Function in Female and Male Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Robin C Shoemaker ◽  
Yu Wang ◽  
Sean Thatcher ◽  
Lisa Cassis
Keyword(s):  
Blood Pressure ◽  
Sexual Dimorphism ◽  
Cardiac Function ◽  
Male Mice ◽  
Reduced Ejection Fraction ◽  
Obesity Hypertension ◽  
Obese Male ◽  
Deficient Mice ◽  
Cmr Imaging

Angiotensin-1-7 (Ang-(1-7)) counteracts angiotensin II through effects at Mas receptors (MasR). We demonstrated that sexual dimorphism of obesity-hypertension was associated with dysregulated production of Ang-(1-7). However, the role of MasR in sexual dimorphism of obesity-hypertension has not been examined. MasR deficient mice have also been reported to exhibit deficits in cardiac function. In this study, we hypothesized that deficiency of the MasR would differentially regulate obesity-hypertension in male versus ( vs ) female mice. In addition, we quantified effects of MasR deficiency on cardiac function in obese male mice. Male and female MasR +/+ and -/- mice were fed a low fat (LF, 10%kcal) or high fat (HF, 60% kcal) diet for 16 weeks, and blood pressure was quantified by radiotelemetry. As demonstrated previously, male MasR +/+ mice (24 hr diastolic blood pressure, DBP: LF, 90 ± 3; HF, 96 ± 2 mmHg; P<0.05), but not females (LF, 85 ± 1; HF, 85 ± 2 mmHg), developed hypertension in response to HF feeding. MasR deficiency converted female HF-fed mice to an obesity-hypertension phenotype (DBP: 92 ± 1 mmHg; P<0.05). Surprisingly, male HF-fed MasR -/- mice exhibited reduced DBP compared to HF-fed MasR +/+ males (90 ± 1 vs 96 ± 2 mmHg; P<0.05). To define mechanisms for reductions in DBP of HF-fed male MasR -/- mice, we performed cardiac magnetic resonance (CMR) imaging in both genotypes at 1 month of HF feeding. MasR -/- mice had significantly reduced ejection fraction (EF) compared to MasR +/+ mice at baseline (51.4 ± 2.5 vs 59.3 ± 2.1%; P<0.05) and after one month of HF-feeding (49.8 ± 2.4 vs 52.6 ± 1.9%; P<0.05). Further, CMR imaging demonstrated a thickening of the ventricle wall in MasR -/- mice with 1 month of HF-feeding. MasR +/+ , but not MasR -/- mice, exhibited diet-induced reductions in EF (by 16%; P<0.05) at 1 month of HF feeding, which were reversed by infusion of Ang-(1-7). These results demonstrate that MasR contributes to sexual dimorphism of obesity-hypertension. Ang-(1-7) protects females from obesity-hypertension through the MasR. In contrast, reductions in DBP in obese male mice with MasR deficiency may arise from deficits in cardiac function. These results suggest that MasR agonists may be effective therapies for obesity-associated cardiovascular conditions.

scholarly journals Neutrophil Elastase Deficiency Ameliorates Myocardial Injury Post Myocardial Infarction in Mice

2021 ◽  
Vol 22 (2) ◽  
pp. 722
Author(s):  
Yukino Ogura ◽  
Kazuko Tajiri ◽  
Nobuyuki Murakoshi ◽  
DongZhu Xu ◽  
Saori Yonebayashi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Neutrophil Elastase ◽  
Myocardial Injury ◽  
Flow Cytometric Analysis ◽  
Akt Signaling ◽  
Border Zone ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Deficient Mice

Neutrophils are recruited into the heart at an early stage following a myocardial infarction (MI). These secrete several proteases, one of them being neutrophil elastase (NE), which promotes inflammatory responses in several disease models. It has been shown that there is an increase in NE activity in patients with MI; however, the role of NE in MI remains unclear. Therefore, the present study aimed to investigate the role of NE in the pathogenesis of MI in mice. NE expression peaked on day 1 in the infarcted hearts. In addition, NE deficiency improved survival and cardiac function post-MI, limiting fibrosis in the noninfarcted myocardium. Sivelestat, an NE inhibitor, also improved survival and cardiac function post-MI. Flow cytometric analysis showed that the numbers of heart-infiltrating neutrophils and inflammatory macrophages (CD11b+F4/80+CD206low cells) were significantly lower in NE-deficient mice than in wild-type (WT) mice. At the border zone between intact and necrotic areas, the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells was lower in NE-deficient mice than in WT mice. Western blot analyses revealed that the expression levels of insulin receptor substrate 1 and phosphorylation of Akt were significantly upregulated in NE-knockout mouse hearts, indicating that NE deficiency might improve cardiac survival by upregulating insulin/Akt signaling post-MI. Thus, NE may enhance myocardial injury by inducing an excessive inflammatory response and suppressing Akt signaling in cardiomyocytes. Inhibition of NE might serve as a novel therapeutic target in the treatment of MI.

scholarly journals Determining the Effects of Combined Liraglutide and Phentermine on Metabolic Parameters, Blood Pressure, and Heart Rate in Lean and Obese Male Mice

Diabetes ◽  
2019 ◽  
Vol 68 (4) ◽  
pp. 683-695 ◽  
Author(s):  
Stephanie E. Simonds ◽  
Jack T. Pryor ◽  
Frank H. Koegler ◽  
Alberte S. Buch-Rasmussen ◽  
Lauren E. Kelly ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Metabolic Parameters ◽  
Male Mice ◽  
Obese Male

scholarly journals Xiao-Qing-Long-Tang Maintains Cardiac Function during Heart Failure with Reduced Ejection Fraction in Salt-Sensitive Rats by Regulating the Imbalance of Cardiac Sympathetic Innervation

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Zhaoyu Li ◽  
Yongcheng Wang ◽  
Yuehua Jiang ◽  
Dufang Ma ◽  
Ping Jiang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Ejection Fraction ◽  
Cardiac Function ◽  
Sympathetic Nerve ◽  
Morphological Changes ◽  
Sympathetic Innervation ◽  
Nerve Endings ◽  
Cardiac Sympathetic Innervation ◽  
Reduced Ejection Fraction

Objective. The anatomical and functional imbalances of sympathetic nerves are associated with cardiovascular disease progression. Xiao-Qing-Long-Tang (XQLT), an ancient Chinese herbal formula, has been used to treat cardiovascular diseases in eastern Asia for thousands of years. We determined the effect of XQLT in maintaining cardiac function during heart failure with reduced ejection fraction (HFrEF) with respect to its neurobiological effects in salt-sensitive rats. Methods. Dahl salt-sensitive (DS) rats were fed a high-salt diet to establish an HFrEF model and were divided into model (DS, administered normal saline) and XQL groups (administrated XQLT) randomly, with SS-13BN rats being used as the control. The bodyweight and blood pressure of rats were observed regularly. Electrocardiogram, echocardiography, and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) were determined to assess cardiac function. The sympathetic tune and myocardial morphological changes were evaluated. Western blot and qRT-PCR were used to assay the expression of the nerve growth factor (NGF) and leukemia inhibitory factor (LIF). Tyrosine hydroxylase (TH), choline acetyltransferase (CHAT), and growth-associated protein 43 (GAP43) were assayed to confirm sympathetic remodeling. The micromorphological changes in cardiac sympathetic nerve endings were observed by transmission electron microscopy. Results. Four weeks after XQLT treatment, cardiac function and bodyweight were higher and blood pressure was lower than that of the DS group. Myocardial noradrenaline (NA) increased, while the plasma NA level decreased significantly. The morphology demonstrated that XQLT significantly alleviated myocardial damage. XQLT decreased the expression of LIF, increased the expression of NGF, enhanced the TH+/GAP43+ and TH+/CHAT + positive nerve fiber density, and improved the TH and GAP43 protein expression, but had no effect on CHAT. Moreover, XQLT improved the micromorphology of sympathetic nerve endings in the myocardium. Conclusion. XQLT maintains cardiac function during HFrEF in salt-sensitive rats, in part, by regulating the imbalance of cardiac sympathetic innervation.

scholarly journals CCR3 deficiency is associated with increased osteoclast activity and reduced cortical bone volume in adult male mice

2020 ◽  
pp. jbc.RA120.015571
Author(s):  
Sara Rosendahl ◽  
Rima Sulniute ◽  
Michaela Eklund ◽  
Cecilia Koskinen Holm ◽  
Marcus J. O. Johansson ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cortical Bone ◽  
Bone Remodeling ◽  
Adult Male ◽  
Chemokine Receptors ◽  
Osteoclast Formation ◽  
Male Mice ◽  
Primary Mouse ◽  
Deficient Mice

Increasing evidence emphasizes the importance of chemokines and chemokine receptors as regulators of bone remodeling. The C-C chemokine receptor 3 (CCR3) is dramatically up-regulated during osteoclastogenesis but the role of CCR3 in osteoclast formation and bone remodeling in adult mice is unknown. Herein, we used bone marrow macrophages (BMM) derived from adult male CCR3-proficient and -deficient mice to study the role of CCR3 in osteoclast formation and activity. CCR3 deficiency was associated with formation of giant hypernucleated osteoclasts, enhanced bone resorption when cultured on bone slices and altered mRNA expression of related chemokine receptors and ligands. Additionally, primary mouse calvarial osteoblasts isolated from CCR3-deficient mice showed increased mRNA expression of the osteoclast activator related gene, receptor activator of nuclear factor kappa-B ligand (Rankl), and osteoblast differentiation associated genes. Micro-computed tomography analyses of femurs from CCR3-deficient mice revealed a bone phenotype that entailed less cortical thickness and volume. Consistent with our in vitro studies, the number of osteoclasts did not differ between the genotypes in vivo. Moreover, an increased endo-cortical osteoid mineralization rate and higher trabecular and cortical bone formation rate was displayed in CCR3-deficient mice. Collectively, our data show that CCR3 deficiency influences osteoblast and osteoclast differentiation and that it is associated with thinner cortical bone in adult male mice.

scholarly journals Response to Role of Hyperleptinemia in the Regulation of Blood Pressure and Cardiac Function

Hypertension ◽  
2014 ◽  
Vol 63 (1) ◽  
Author(s):  
Anne-Maj Samuelsson ◽  
James Clark ◽  
Olena Rudyk ◽  
Michael J. Shattock ◽  
Sung Eun Bae ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Function ◽  
Regulation Of Blood Pressure

scholarly journals Role of the Multidomain Protein Spinophilin in Blood Pressure and Cardiac Function Regulation

Hypertension ◽  
2008 ◽  
Vol 52 (4) ◽  
pp. 702-707 ◽  
Author(s):  
Andrey C. da Costa-Goncalves ◽  
Jens Tank ◽  
Ralph Plehm ◽  
Andre Diedrich ◽  
Mihail Todiras ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Function ◽  
Multidomain Protein

Adenosine as a mediator of macula densa-dependent inhibition of renin secretion

2006 ◽  
Vol 290 (5) ◽  
pp. F1016-F1023 ◽  
Author(s):  
Soo Mi Kim ◽  
Diane Mizel ◽  
Yuning G. Huang ◽  
Josie P. Briggs ◽  
Jurgen Schnermann
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Plasma Renin ◽  
Macula Densa ◽  
Renin Secretion ◽  
Nacl Transport ◽  
Dependent Inhibition ◽  
Deficient Mice ◽  
Stimulation Of

Adenosine acting through A1 adenosine receptors (A1AR) has been shown previously to be required for the vasoconstriction elicited by high luminal NaCl concentrations at the macula densa (MD). The present experiments were performed to investigate a possible role of A1AR in MD control of renin secretion in conscious wild-type (WT) and A1AR-deficient mice. The intravenous injection of NaCl (5% body wt) reduced plasma renin concentration (PRC; ng ANG I·ml−1·h−1) from 1,479 ± 129 to 711 ± 77 ( P < 0.0001; n = 18) in WT mice but did not significantly change PRC in A1AR−/− mice (1,352 ± 168 during control vs. 1,744 ± 294 following NaCl; P = 0.19; n = 17). NaCl injections also caused a significant reduction in PRC in β1/β2-adrenergic receptor−/− mice (298 ± 47 vs. 183 ± 42; P = 0.03; n = 6). Injections of isotonic NaHCO3 (5% body wt) elicited significant increases in PRC in both WT and A1AR−/− mice. NaCl as well as NaHCO3 injections were accompanied by transient increases in blood pressure, heart rate, and activity that were similar in WT and A1AR−/− mice. The increase in PRC caused by an intraperitoneal injection of furosemide (40 mg/kg) was comparable in WT and A1AR−/− mice, and it was accompanied by similar transient increases in blood pressure, heart rate, and activity. Similarly, the stimulation of PRC caused by hydralazine was the same in WT and A1AR−/− mice. We conclude that the inhibition of renin secretion in response to an increase in NaCl at the MD requires A1AR and therefore appears to be adenosine dependent, whereas the stimulation of renin secretion during reductions in MD NaCl transport or arterial pressure does not require functional A1AR.

scholarly journals Deficiency of Angiotensinogen in Hepatocytes Markedly Decreases Blood Pressure in Lean and Obese Male Mice

Hypertension ◽  
2015 ◽  
Vol 66 (4) ◽  
pp. 836-842 ◽  
Author(s):  
Frederique Yiannikouris ◽  
Yu Wang ◽  
Robin Shoemaker ◽  
Nika Larian ◽  
Joel Thompson ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Male Mice ◽  
Obese Male

P3509Leukocyte derived tumour necrosis factor modulates cardiac function in health and disease

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Walker ◽  
A Gutierrez Del Arroyo ◽  
J Sanchez ◽  
G L Ackland
Keyword(s):  
Ejection Fraction ◽  
Cardiac Function ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Cardiac Injury ◽  
Cardiac Cells ◽  
Health And Disease ◽  
Deficient Mice ◽  
Necrosis Factor

Abstract Purpose Tumour necrosis factor alpha (TNFα) regulates both normal and pathophysiological cardiac function. The regulatory role of TNFα derived from different sources (leukocyte versus cardiac cells) in cardiac physiology is unclear. Deficiency of iRhom2 protein prevents circulating immune cells from shedding TNFα (and CD62L, an adhesion molecule essential for effective immune function). Here we investigated the role of leukocyte derived TNFα in constitutive cardiac function and after cardiac injury. Methods Adult iRhom2-deficient mice (KO) and wildtype (Wt) littermates, of both genders, underwent echocardiography to assess cardiac physiologic function at least 1 week before receiving a single dose of isoproterenol (300mg/kg IP) to induce cellular death in 10% of the cardiomyoctes [1]. Cardiac echocardiography was repeated 36 hours after isoproterenol. Peripheral and cardiac-resident leukocytes were phenotyped by flow cytometry and molecular markers of cardiac stress (atrial and brain natriuretic protein, ANP, BNP) and inflammation (NFkB) were quantified using RT-PCR. Results Peripheral leukocytes from iRhom2 KO mice failed to shed CD62L in response to isoproterenol induced cardiac injury (e.g. neutrophils CD62L Mean Fluorescence Intensity KO: 9149±4616, Wt: 972±558, p<0.0001, n=9). iRhom2-deficient mice had higher cardiac output at baseline (KO 23±2 mL/min, n=11) compared to their wildtype littermates (Wt 18±3 mL/min, n=9). Wild type mice increased contractility after isoproterenol (Wt ejection fraction: baseline 60±6%, isoproterenol 68±6%, n=8) whilst iRhom2-deficient mice were unable to (KO ejection fraction: baseline 66±9%, isoproterenol 61±5%, n=8). ANP and BNP mRNA were elevated in ventricular tissue of iRhom2-knockout mice after isoproterenol, when compared to naïve tissue (ANP 2ΔCT: 3x increase, BNP 2ΔCT: 1.6x increase) whereas only ANP was elevated in wildtypes (ANP 2ΔCT: 2.7x increase, BNP 2ΔCT: 0.9x increase). No difference in immune cell infiltration of ventricular cardiac tissue was observed (number of CD45+ cells KO: 3014±3482, Wt: 2555±1411, p=0.7, n=9) NFkB mRNA was upregulated at baseline (2ΔCT KO: 0.2±0.08, Wt: 0.1±0.09) suggesting constitutive cardiac inflammation in iRhom2-deficient mice. Conclusions Inability to shed CD62L and TNFα is associated with constitutive and acquired cardiac dysfunction in iRhom2-deficient mice. These data support the hypothesis that leukocyte-derived TNFα is required for maintaining cardiac function in health and disease. Acknowledgement/Funding National Institute of Academic Anaesthesia/Royal College of Anaesthetists/British Journal of Anaesthesia; National Institute for Health Research

Blood pressure maintenance in NHE3-deficient mice with transgenic expression of NHE3 in small intestine

2005 ◽  
Vol 288 (3) ◽  
pp. R685-R691 ◽  
Author(s):  
William T. Noonan ◽  
Alison L. Woo ◽  
Michelle L. Nieman ◽  
Vikram Prasad ◽  
Patrick J. Schultheis ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Small Intestine ◽  
Transgenic Expression ◽  
Specific Effects ◽  
Lower Blood ◽  
Blood Pressures ◽  
Pressure Natriuresis ◽  
Deficient Mice ◽  
Robust Response

NHE3 Na+/H+ exchanger knockout ( Nhe3−/−) mice have severe absorptive deficits in the kidney proximal tubule and intestinal tract. The resulting hypovolemia has confounded efforts to carefully evaluate the specific effects of NHE3 deficiency on kidney function. Development of mice with transgenic expression of NHE3 in the small intestine (tg Nhe3−/−) has allowed us to analyze the role of renal NHE3 in overall maintenance of blood pressure, pressure natriuresis, and autoregulation of both glomerular filtration rate (GFR) and renal blood flow (RBF). Ambulatory blood pressure, measured by telemetry, was lower in tg Nhe3−/− mice than in wild-type controls (tg Nhe3+/+) when the mice were maintained on a normal NaCl diet but was normalized when they were provided with a high NaCl intake. Furthermore, administration of the AT1-receptor blocker losartan showed that circulating ANG II plays a major role in maintaining blood pressure in tg Nhe3−/− mice fed normal NaCl but not in those receiving high NaCl. Clearance studies revealed a blunted pressure-natriuresis response in tg Nhe3−/− mice at lower blood pressures but a robust response at higher blood pressures. Autoregulation of GFR and RBF was normal in tg Nhe3−/− mice. These results show that dietary NaCl loading normalizes blood pressure in awake tg Nhe3−/− mice and that alterations in NHE3 activity are not essential for normal autoregulation of GFR and RBF. Furthermore, the data strongly support the hypothesis that NHE3 plays an important role in the diuretic and natriuretic responses to increases in blood pressure but also show that mechanisms not involving NHE3 mediate pressure natriuresis in the higher range of blood pressures studied.

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