Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension

Henriques‐Coelho, Tiago; Correia‐Pinto, Jorge; Roncon‐Albuquerque, Roberto; Baptista, Maria João; Lourenço, André P.; Oliveira, Sílvia Marta; Brandão-Nogueira, Ana; Teles, Antónia; Fortunato, José M.; Leite‐Moreira, Adelino F.

doi:10.1152/ajpheart.01122.2003

Cited by 57 publications

(37 citation statements)

References 37 publications

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“…Relative quantification of mRNA Two-step Real-time RT-PCR was performed as previously described [14,15,33,40]. Briefly, after total mRNA extraction (no.…”

Section: Molecular Studiesmentioning

confidence: 99%

Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension

et al. 2009

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Although pulmonary hypertension (PH) selectively overloads the right ventricle (RV), neuroendocrine activation and intrinsic myocardial dysfunction have been described in the left ventricle (LV). In order to establish the timing of LV dysfunction development in PH and to clarify underlying molecular changes, Wistar rats were studied 4 and 6 weeks after subcutaneous injection of monocrotaline (MCT) 60 mg/kg (MCT-4, n = 11; MCT-6, n = 11) or vehicle (Ctrl-4, n = 11; Ctrl-6, n = 11). Acute single beat stepwise increases of systolic pressure were performed from baseline to isovolumetric (LVPiso). This hemodynamic stress was used to detect early changes in LV performance. Neurohumoral activation was evaluated by measuring angiotensin-converting enzyme (ACE) and endothelin-1 (ET-1) LV mRNA levels. Cardiomyocyte apoptosis was evaluated by TUNEL assay. Extracellular matrix composition was evaluated by tenascin-C mRNA levels and interstitial collagen content. Myosin heavy chain (MHC) composition of the LV was studied by protein quantification. MCT treatment increased RV pressures and RV/LV weight ratio, without changing LV end-diastolic pressures or dimensions. Baseline LV dysfunction were present only in MCT-6 rats. Afterload elevations prolonged s and upward-shifted end-diastolic pressure dimension relations in MCT-4 and even more in MCT-6. MHC-isoform switch, ACE upregulation and cardiomyocyte apoptosis were present in both MCT groups. Rats with severe PH develop LV dysfunction associated with ET-1 and tenascin-C overexpression. Diastolic dysfunction, however, could be elicited at earlier stages in response to hemodynamic stress, when only LV molecular changes, such as MHC isoform switch, ACE upregulation, and myocardial apoptosis were present.

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“…Relative quantification of mRNA Two-step Real-time RT-PCR was performed as previously described [14,15,33,40]. Briefly, after total mRNA extraction (no.…”

Section: Molecular Studiesmentioning

confidence: 99%

Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension

et al. 2009

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“…The Wistar rat model has been used for heart-rate analysis research by some centres (Moraru et al 2004, Murasato et al 1998, and it is a model particularly well known at our institution in cardiovascular research (Henriques-Coelho et al 2004, Lourenço et al 2006. Moraru et al (2004) have studied linear and nonlinear HR dynamics in rats recovering from an episode of cardiac arrest.…”

Section: Introductionmentioning

confidence: 99%

The Obestatin/Ghrelin System as a Novel Regulatory Mechanism of Iris Muscle Contraction

Rocha‐Sousa

Falcão‐Reis

Leite‐Moreira

2008

Current Eye Research

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The objective of this study was the assessment of heart-rate (HR) dynamics with linear and nonlinear methods during episodes of mechanical ventilation and acute anoxia in rats. Namely, to assess whether linear and nonlinear HR analysis was able to discriminate acute anoxia from baseline in rats and if this was consistent with human foetal and adult studies. Five HR segments of 1 min duration, during baseline recording, mechanical ventilation and first, second and third minutes of induced acute anoxia, were analysed in ten adult Wistar rats. Linear time and frequency domain and nonlinear methods were used, namely mean HR (mHR), long-term irregularity (LTI), interval index (II), low frequency (LF) and high frequency (HF), approximate entropy (ApEn) and sample entropy (SampEn). New parameters for the entropy indices are proposed for the analysis of rats' HR. Bootstrap percentile confidence intervals and nonparametric statistical tests were used in the evaluation of the differences between segments. During mechanical ventilation a clear spectral band was detectable at the ventilation rate, but mHR, II and the 'new' entropy indices were the only significantly changed indices. In the transition from baseline-mechanical-ventilation to mechanical-ventilationinduced anoxia, a statistically significant decrease of mHR, II and entropy indices was observed, clearly discriminating these two instances, whereas most linear indices increased. With continued anoxia, most linear indices decreased significantly, whereas entropy remained stably low. These results are consistent with other foetal human and non-human studies and evidence that the rat model may be used for further research on linear and nonlinear analysis of heart-rate dynamics. The transition from baseline to acute anoxia was encompassed by signs of increased activation of the autonomic nervous system sympathetic branch, and decreased or blunted activity of the HR complexity regulatory centres.

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“…Increased levels of circulating ghrelin are observed in IPAH (91). However, paradoxically, in MCT or hypoxic rat models the administration of ghrelin reduces PH (92,93). Thus, ghrelin is protective in rodent models but elevated in IPAH.…”

Section: Synthesis Of the Literature On Sex Bias Mediated By The Neurmentioning

confidence: 99%

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Sehgal

Yang

Miller

2015

Mol Med

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Pulmonary hypertension (PH) is a disease with high morbidity and mortality. The prevalence of idiopathic pulmonary arterial hypertension (IPAH) and hereditary pulmonary arterial hypertension (HPAH) is approximately two-to four-fold higher in women than in men. Paradoxically, there is an opposite male bias in typical rodent models of PH (chronic hypoxia or monocrotaline); in these models, administration of estrogenic compounds (for example, estradiol-17β [E2]) is protective. Further complexities are observed in humans ingesting anorexigens (female bias) and in rodent models, such as after hypoxia plus SU5416/Sugen (little sex bias) or involving serotonin transporter overexpression or dexfenfluramine administration (female bias). These complexities in sex bias in PH remain incompletely understood. We recently discovered that conditional deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells abrogated the male bias in PH in hypoxic mice and that late-stage obliterative lesions in patients of both sexes with IPAH and HPAH showed reduced STAT5a/b, reduced Tyr-P-STAT5 and reduced B-cell lymphoma 6 protein (BCL6). In trying to understand the significance of these observations, we realized that there existed a wellcharacterized E2-sensitive central neuroendocrine mechanism of sex bias, studied over the last 40 years, that, at its peripheral end, culminated in species-specific male ("pulsatile") versus female ("more continuous") temporal patterns of circulating growth hormone (GH) levels leading to male versus female patterned activation of STAT5a/b in peripheral tissues and thus sex-biased expression of hundreds of genes. In this report, we consider the contribution of this neuroendocrine mechanism (hypothalamus-GH-STAT5) in the generation of sex bias in different PH situations.

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Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension

Cited by 57 publications

References 37 publications

Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension

Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension

The Obestatin/Ghrelin System as a Novel Regulatory Mechanism of Iris Muscle Contraction

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

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