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Abnormal baroreflex function is dissociated from central angiotensin II receptor expression in chronic heart failure.

ABSTRACT: Neurohumoral disturbances characterize chronic heart failure (CHF) and are reflected, in part, as impairment of baroreflex sensitivity (BRS) and sympathetic function. However, the mechanisms that trigger these neurohumoral abnormalities in CHF are not clear. We hypothesized that the BRS is blunted early in CHF and that the humoral effects occur later and contribute to progressive loss of cardiovascular control in CHF. We assessed the BRS (beats/min per mmHg) and recorded renal sympathetic nerve activity (RSNA) in four groups of conscious rabbits at varying time intervals: control, 1-week CHF, 2-week CHF, and 3-week CHF. Chronic heart failure was induced by ventricular pacing at 360 beats/min and was assessed by echocardiography. Arterial blood pressure and heart rate were recorded by an implanted telemetric device and RSNA through an implanted electrode. A significant fall in the ejection fraction, fractional shortening, and an increase in left ventricular end-systolic diameter and left ventricular end-diastolic diameter were observed in all CHF groups. The BRS was significantly reduced in all the CHF groups with no significant change in the basal RSNA (% of maximum) after 1 week of pacing; a small but insignificant rise in RSNA was seen at 2 weeks, and a significant rise in RSNA was observed at 3 weeks. Angiotensin II type 1 (AT-1) receptor protein (Western Blot) and mRNA (reverse transcriptase-polymerase chain reaction) expression in the rostral ventrolateral medulla exhibited a progressive increase with the duration of CHF, reaching significance after 3 weeks, the same time point in which RSNA was significantly elevated. These data are the first to examine early changes in central AT-1 receptors in CHF and suggest that the fall in BRS and hemodynamic changes occur early in the development of CHF followed by sympathoexcitation and overexpression of AT-1 receptors with the progression of CHF, causing further impairment of cardiovascular control.

SUBMITTER: Fahim M

PROVIDER: S-EPMC3281308 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Abnormal baroreflex function is dissociated from central angiotensin II receptor expression in chronic heart failure.

Fahim Mohammad M Gao Lie L Mousa Tarek M TM Liu Dongmei D Cornish Kurtis G KG Zucker Irving H IH

Shock (Augusta, Ga.) 20120301 3

Neurohumoral disturbances characterize chronic heart failure (CHF) and are reflected, in part, as impairment of baroreflex sensitivity (BRS) and sympathetic function. However, the mechanisms that trigger these neurohumoral abnormalities in CHF are not clear. We hypothesized that the BRS is blunted early in CHF and that the humoral effects occur later and contribute to progressive loss of cardiovascular control in CHF. We assessed the BRS (beats/min per mmHg) and recorded renal sympathetic nerve ...[more]

PMID: 22258229

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Project description:BACKGROUND AND PURPOSE:Mitochondrial dysfunction plays a role in the progression of cardiovascular diseases including heart failure. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins), which inhibit ROS synthesis, show cardioprotective effects in chronic heart failure. However, the beneficial role of statins in mitochondrial protection in heart failure remains unclear. EXPERIMENTAL APPROACH:Rats were treated with angiotensin II (1.5 mg·kg-1 ·day-1 ) or co-administered simvastatin (oral, 10 mg·kg-1 ) for 14 days; and then administration was stopped for the following 14 days. Cardiac structure/function was examined by wheat germ agglutinin staining and echocardiography. Mitochondrial morphology and the numbers of lipid droplets, lysosomes, autophagosomes, and mitophagosomes were determined by transmission electron microscopy. Human cardiomyocytes were stimulated, and intracellular ROS and mitochondrial membrane potential (??m ) changes were measured by flow cytometry and JC-1 staining, respectively. Autophagy and mitophagy-related and mitochondria-regulated apoptotic proteins were identified by immunohistochemistry and western blotting. KEY RESULTS:Simvastatin significantly reduced ROS production and attenuated the disruption of ??m . Simvastatin induced the accumulation of lipid droplets to provide energy for maintaining mitochondrial function, promoted autophagy and mitophagy, and inhibited mitochondria-mediated apoptosis. These findings suggest that mitochondrial protection mediated by simvastatin plays a therapeutic role in heart failure prevention by modulating antioxidant status and promoting energy supplies for autophagy and mitophagy to inhibit mitochondrial damage and cardiomyocyte apoptosis. CONCLUSION AND IMPLICATIONS:Mitochondria play a key role in mediating heart failure progression. Simvastatin attenuated heart failure, induced by angiotensin II, via mitochondrial protection and might provide a new therapy to prevent heart failure.

Project description:Angiotensin-converting enzyme 2 (ACE2), a new component of the brain renin-angiotensin system, has been suggested to participate in the central regulation of blood pressure (BP). To clarify the relationship between ACE2 and other brain renin-angiotensin system components, we hypothesized that central angiotensin II type 1 receptors reduce ACE2 expression/activity in hypertensive mice, thereby impairing baroreflex function and promoting hypertension. To test this hypothesis, chronically hypertensive mice (RA) with elevated angiotensin II levels were treated with losartan (angiotensin II type 1 receptor blocker) or PD123319 (angiotensin II type 2 antagonist; 10 mg/kg per day, SC) for 2 weeks. Baseline spontaneous baroreflex sensitivity and brain ACE2 activity were dramatically decreased in RA compared with nontransgenic mice, whereas peripheral ACE2 activity/expression remained unaffected. Losartan, but not PD123319, increased central ACE2 activity, spontaneous baroreflex sensitivity, and normalized BP in RA mice. To confirm the critical role of central ACE2 in BP regulation, we generated a triple-transgenic model with brain ACE2 overexpression on a hypertensive RA background. Triple-transgenic-model mice exhibit lower BP and blunted water intake versus RA, suggesting lower brain angiotensin II levels. Moreover, the impaired spontaneous baroreflex sensitivity, parasympathetic tone, and increased sympathetic drive, observed in RA, were normalized in triple-transgenic-model mice. These data suggest that angiotensin II type 1 receptors inhibit ACE2 activity in RA mice brain, thus contributing to the maintenance of hypertension. In addition, overexpression of ACE2 in the brain reduces hypertension by improving arterial baroreflex and autonomic function. Together, our data suggest that angiotensin II type 1 receptor-mediated ACE2 inhibition impairs baroreflex function and support a critical role for ACE2 in the central regulation of BP and the development of hypertension.

Project description:AimsLarge outcome studies demonstrated a reduction of heart failure hospitalization or cardiovascular death in patients with chronic heart failure (CHF). The renin-angiotensin system (RAS) is a key player in fluid and sodium regulation. The classic angiotensin-converting enzyme-angiotensin II-angiotensin-1 receptor axis (Ang I-ACE-Ang II receptor axis) is predominantly angiotensin II (Ang-II) induced and promotes vasoconstriction. In contrast, the angiotensin-converting-enzyme-2-angiotensin-(1-7)-Mas axis (Mas-axis) is mediated by the metabolites angiotensin-1-7 (Ang-(1-7)) and angtiotensin-1-5 (Ang-(1-5)) and exerts cardioprotective effects.MethodsWe previously investigated the effect of empagliflozin on the systemic haemodynamic in patients with stable CHF (NYHA II-III) in a randomized placebo-controlled clinical trial 'Analysing the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure (ELSI)'. In a post hoc analysis, we now analysed whether empagliflozin has an effect on the RAS by measuring detailed RAS profiles (LC-MS/MS-based approach) in 72 patients from ELSI. We compared RAS parameters after 1-month and 3-months treatment with empagliflozin or placebo to baseline. The secondary goal was to analyse whether the effect of empagliflozin on RAS parameters was dependent on angiotensin-receptor-blocking (ARB) or angiotensin-converting-enzyme-inhibitor (ACEI) co-medication.ResultsEmpagliflozin medication induced a significant rise in Ang-II [68.5 pmol/L (21.3-324.2) vs. 131.5 pmol/L (34.9-564.0), P = 0.001], angiotensin-I (Ang-I) [78.7 pmol/L (21.5-236.6) vs. 125.9 pmol/L (52.6-512.9), P < 0.001], Ang-(1-7) [3.0 pmol/L (3.0-15.0) vs. 10.1 pmol/L (3.0-31.3), P = 0.006], and Ang-(1-5) [5.4 pmol/L (2.0-22.9) vs. 9.9 pmol/L (2.8-36.4), P = 0.004], which was not observed in the placebo group (baseline to 3-months treatment). A significant rise in Ang-II (206.4 pmol/L (64.2-750.6) vs. 568.2 pmol/L (164.7-1616.4), P = 0.001), Ang-(1-7) (3.0 pmol/L (3.0-14.1) vs. 15.0 pmol/L (3.0-31.3), P = 0.017), and Ang-(1-5) [12.2 pmol/L (3.8-46.6) vs. 36.4 pmol/L (11.1-90.7), P = 0.001] under empagliflozin treatment was only seen in the subgroup of patients with ARB co-medication, whereas no change of Ang-II (16.7 pmol/L (2.0-60.8) vs. 26.4 pmol/L (10.7-63.4), P = 0.469), Ang-(1-7) (6.6 pmol/L (3.0-20.7) vs. 10.5 pmol/L (3.0-50.5), P = 0.221), and Ang-(1-5) (2.7 pmol/L (2.0-8.4) vs. 2.8 pmol/L (2.0-6.9), P = 0.851) was observed in patients with empagliflozin that were on ACEI co-medication (baseline to 3-months treatment).ConclusionsOur data indicate that empagliflozin might lead to an activation of both the Ang I-ACE-Ang II receptor axis and the Mas-axis pathway. Activation of the Ang I-ACE-Ang II receptor axis and the protective Mas-axis pathway after initiating treatment with empagliflozin was only seen in patients with ARB co-medication, in contrast to co-medication with ACEI.

Dataset Information

Abnormal baroreflex function is dissociated from central angiotensin II receptor expression in chronic heart failure.

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Abnormal baroreflex function is dissociated from central angiotensin II receptor expression in chronic heart failure.

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