Abstract 185: Transient Neonatal High Oxygen Exposure Leads to Cardiac Dysfunction and Renin Angiotensin System Activation in Rats

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Mariane Bertagnolli ◽  
Fanny Huyard ◽  
Anik Cloutier ◽  
Megan Sutherland ◽  
Marie-Amélie Lukaszewski ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Heart Development ◽  
Heart Function ◽  
Renin Angiotensin System ◽  
Left Ventricular ◽  
High Oxygen ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Ras Activation ◽  
High O2

Preterm infants are exposed to high oxygen (O2) pressure (relative to intrauterine levels) leading to systemic oxidative stress and impaired vascular development; as children and adults, preterm born subjects have higher blood pressure. In rats, high O2 exposure induces vascular dysfunction, in part mediated by the renin angiotensin system (RAS). However, impact of neonatal high O2 exposure on heart development and whether RAS activation prevails in the heart is unknown. We aimed to assess early heart alterations and activation of RAS after neonatal high O2 exposure. METHODS AND RESULTS: Sprague-Dawley pups were kept with their mother in 80% O2 (O2, n=8) or room air (Ctrl, n=8) from days 3-10 of life. Hearts were extracted at day 3 (pre O2-exposure, P3), day 5 (during, P5), 10 (after, P10) and 4 wks to assess myocardium hypertrophy (HE), fibrosis (Masson’s trichrome) and RAS components gene expressions by RT-PCR. Echocardiography was performed at 4 weeks to assess heart function. RAS components mRNA expression in O2 vs Ctrls shows up-regulation of AT1a and ACE2 genes at P5 (AT1a: 152±28 vs 58±16/ACE2: 140±20 vs 77±6% of P3) and P10 (AT1a: 374±35 vs 250±30 /ACE2: 326±70 vs 208±18% of P3) relative to values at P3. With age, AT1b and AT2 expressions decrease in Ctrls, whereas are maintained in O2-exposed rats to values similar to P3 (Ctrl vs O2, P5: AT1b: 18±5 vs 71±12/AT2: 48±20 vs 120±16; P10: AT1b: 33±9 vs 105±26/AT2: 27±8 vs 77±7% of P3). At P10, cardiomyocyte surface area is increased in O2 vs Ctrls (4.9±0.2 vs 2.9±0.1 μm2). At 4 wks, O2 group show increased fibrosis (49±4 vs 29±2 % pixels), left ventricular (LV) cavity diameter (3.6±0.2 vs 3.0±0.1 mm) and systolic dysfunction by decreased fraction of shortening (39±2 vs 47±2 %). AT1b gene expression (2.6±1.7 vs 0.3±0.2) is increased and AT2 receptor (7.5±0.9 vs 6.0±0.6) is decreased in O2 group vs Ctrl. CONCLUSION: Neonatal O2 exposure activates RAS in hearts. AT1 receptor is up-regulated at all ages studied in O2-exposed rat hearts while AT2 is up-regulated at P5 and P10. At 4 wks, AT1/AT2 imbalance prevails in O2 group hearts along with LV dysfunction and enhanced fibrosis and hypertrophy. RAS activation by neonatal O2-exposure might significantly impact in heart development and programming of cardiac dysfunction in rats.

scholarly journals Transient Neonatal High Oxygen Exposure Leads to Early Adult Cardiac Dysfunction, Remodeling, and Activation of the Renin–Angiotensin System

Hypertension ◽  
2014 ◽  
Vol 63 (1) ◽  
pp. 143-150 ◽  
Author(s):  
Mariane Bertagnolli ◽  
Fanny Huyard ◽  
Anik Cloutier ◽  
Zackary Anstey ◽  
Julie-Émilie Huot-Marchand ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Renin Angiotensin System ◽  
High Oxygen ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Oxygen Exposure

P4473Brain renin-angiotensin system blockade with firibastat, an orally active, central acting aminopeptidase A inhibitor prodrug prevents cardiac dysfunction after myocardial infarction in mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Boitard-Joanne ◽  
Y Marc ◽  
M Keck ◽  
N Mougenot ◽  
O Agbulut ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Dysfunction ◽  
Enzyme Inhibitor ◽  
Diastolic Pressure ◽  
Renin Angiotensin System ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Aminopeptidase A

Abstract Introduction Brain renin-angiotensin system (RAS) hyperactivity has been implicated in sympathetic hyperactivity and progressive left ventricular (LV) dysfunction after myocardial infarction (MI). Brain angiotensin III, generated by aminopeptidase A (APA), is one of the main effector peptides of the brain RAS in the control of cardiac function. Purpose We hypothesized that orally administered firibastat (previously named RB150), an orally central acting APA inhibitor prodrug, would attenuate heart failure (HF) development after MI in mice, by blocking brain RAS hyperactivity. Methods Two days after MI induced by the left anterior descending artery ligation, adult male CD1 mice were randomized to three groups, for four to eight weeks of oral treatment with vehicle (MI+vehicle), firibastat (150 mg/kg; MI+firibastat) or the angiotensin I converting enzyme inhibitor enalapril (1 mg/kg; MI+enalapril) as a positive control. Results From one to four weeks post-MI, brain APA hyperactivity occurred, contributing to brain RAS hyperactivity. Firibastat treatment during four weeks after MI normalized brain APA hyperactivity, with a return to the control values measured in the sham group. Four and six weeks after MI, MI+firibastat mice had a significant lower LV end-diastolic pressure, LV end-systolic diameter and volume, and a higher LV ejection fraction than MI+vehicle mice. Moreover, the mRNA levels of biomarkers of HF (Myh7, Bnp and Anf) were significantly lower following firibastat treatment. For a similar infarct size, the peri-infarct area of MI+firibastat mice displayed lower levels of mRNA for markers of fibrosis such Ctgf and collagen types I and III than MI+vehicle mice. Conclusions Chronic oral firibastat administration after MI in mice normalizes brain APA hyperactivity, thereby normalizing brain RAS hyperactivity, whilst preventing cardiac dysfunction and attenuating cardiac hypertrophy and fibrosis. Acknowledgement/Funding INSERM, College de France, ANR LabCom, and Quantum Genomics

scholarly journals Cardiac-specific suppression of NF-κB signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system

2014 ◽  
Vol 307 (7) ◽  
pp. H1036-H1045 ◽  
Author(s):  
Candice M. Thomas ◽  
Qian Chen Yong ◽  
Rodolfo M. Rosa ◽  
Rachid Seqqat ◽  
Shanthi Gopal ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Heart Function ◽  
Renin Angiotensin System ◽  
Receptor Expression ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Transgenic Mouse Line ◽  
Plasmic Reticulum ◽  
Nondiabetic Control

Activation of NF-κB signaling in the heart may be protective or deleterious depending on the pathological context. In diabetes, the role of NF-κB in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-κB modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated IκB-α in the heart (3M mice), which prevented activation of canonical NF-κB signaling. Diabetes was developed by streptozotocin injections in wild-type (WT) and 3M mice. Diabetic WT mice developed systolic and diastolic cardiac dysfunction by the 12th week, as measured by echocardiography. In contrast, cardiac function was preserved in 3M mice up to 24 wk of diabetes. Diabetes induced an elevation in cardiac oxidative stress in diabetic WT mice but not 3M mice compared with nondiabetic control mice. In diabetic WT mice, an increase in the phospholamban/sarco(endo)plasmic reticulum Ca2+-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca2+ handling. Significantly, renin-angiotensin system activity was suppressed in diabetic 3M mice compared with an increase in WT animals. In conclusion, these results demonstrate that inhibition of NF-κB signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca2+ handling and inhibition of the cardiac renin-angiotensin system.

Chronic administration of angiotensin II receptor antagonist, TCV-116, in cardiomyopathic hamsters

1994 ◽  
Vol 267 (6) ◽  
pp. H2297-H2304 ◽  
Author(s):  
F. Nakamura ◽  
M. Nagano ◽  
R. Kobayashi ◽  
J. Higaki ◽  
H. Mikami ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Receptor Antagonist ◽  
Cardiac Dysfunction ◽  
Renin Angiotensin System ◽  
Left Ventricular ◽  
Lv Function ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
At1 Antagonist

We examined whether specific blockade of the renin-angiotensin system is beneficial for the treatment of cardiac dysfunction in heart failure. The angiotensin II type-1 (AT1) receptor antagonist TCV-116 (10 mg.kg-1.day-1) or its vehicle was given orally to UM-X 7.1 cardiomyopathic (CM) and normal Golden Syrian (GS) hamsters for 8 wk. Plasma and cardiac angiotensin II levels were significantly higher in CM than in GS hamsters. The CM heart showed a smaller response of left ventricular (LV) pressure and first derivative of maximal LV pressure (+dP/dtmax) to the elevation of perfusion pressure (from 60 to 120 cmH2O) in Langendorff-perfused than in GS heart. Treatment with TCV-116 did not affect LV function in GS but significantly improved cardiac contractility in CM hamsters. These results suggest that the renin-angiotensin system plays an important role in the development of cardiac dysfunction due to cardiomyopathy. Blockade of this system by the AT1 antagonist TCV-116 appears to be useful in the prevention of heart failure.

Active renin and angiotensinogen in cardiac interstitial fluid after myocardial infarction

1999 ◽  
Vol 276 (6) ◽  
pp. H1818-H1826 ◽  
Author(s):  
Alan T. Hirsch ◽  
John A. Opsahl ◽  
Mary M. Lunzer ◽  
Stephen A. Katz
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Hypertrophy ◽  
Infarct Size ◽  
Interstitial Fluid ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Left Ventricular ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Active Renin

The renin-angiotensin system promotes cardiac hypertrophy after myocardial infarction. The purpose of this study was to measure renin and angiotensinogen in plasma and myocardium 10 days after myocardial infarction. Infarction involving 45 ± 4% of left ventricular circumference with accompanying hypertrophy was induced in rats ( n = 14). Plasma and myocardial renin were increased after infarction compared with sham controls ( n = 8) (27.4 ± 3.2 vs. 7.5 ± 1.8 ng ANG I ⋅ ml plasma ⋅ h−1, P < 0.0002; and 8.8 ± 1.6 vs. 2.5 ± 0.1 ng ANG I ⋅ g myocardium−1 ⋅ h−1, P < 0.008, respectively). After infarction, myocardial renin was correlated with infarct size ( r = 0.62, P < 0.02) and plasma renin ( r = 0.55, P < 0.04). Plasma angiotensinogen decreased in infarct animals, but myocardial angiotensinogen was not different from shams (1.1 ± 0.08 vs. 2.03 ± 0.06 nM/ml plasma, P < 0.002; and 0.081 ± 0.008 vs. 0.070 ± 0.004 nM/g myocardium, respectively). In conclusion, myocardial renin increased after infarction in proportion to plasma renin and infarct size, and myocardial angiotensinogen was maintained after infarction despite decreased plasma angiotensinogen and increased levels of myocardial renin.

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