RESUMEN
ABSTRACT: Angiotensin (Ang)-(1-7) is a cardioprotective peptide of the renin-angiotensin system. Prepuberty has been considered as a later susceptible window of development, and stressful factors in this life phase can induce chronic diseases in adulthood. We aimed to investigate whether the treatment with Ang-(1-7) during the prepuberty could attenuate the development of hypertension and cardiac injury in adult spontaneously hypertensive rats (SHRs). SHRs were treated with Ang-(1-7) (24 µg/kg/h) from age 4 to 7 weeks. Systolic blood pressure was measured by tail-cuff plethysmography up to 17th week. Thereafter, echocardiography was performed, and the rats were euthanized for the collection of tissues and blood. Ang-(1-7) did not change the systolic blood pressure but reduced the septal and posterior wall thickness, and cardiomyocyte hypertrophy and fibrosis in SHR. In addition, Ang-(1-7) reduced the gene expression of atrial natriuretic peptide and brain natriuretic peptide, increased the metalloproteinase 9 expression, and reduced the extracellular signal-regulated kinases 1/2 phosphorylation. Ang-(1-7) also prevented the reduction of Mas receptor but did not change the protein expression of angiotensin-converting enzyme, angiotensin-converting enzyme 2, AT1, and AT2. The treatment with Ang-(1-7) decreased the malondialdehyde (MDA) levels and increased superoxide dismutase-1 and catalase activities and protein expression of catalase. Our findings demonstrate that the treatment of SHR with Ang-(1-7) for 3 weeks early in life promotes beneficial effects in the heart later in life, even without altering blood pressure, through mechanisms involving the reduction of oxidative stress and ERK1/2 phosphorylation. In addition, this study supports the prepuberty as an important programming window.
Asunto(s)
Angiotensina I , Presión Sanguínea , Cardiomegalia , Hipertensión , Estrés Oxidativo , Fragmentos de Péptidos , Ratas Endogámicas SHR , Animales , Angiotensina I/farmacología , Fragmentos de Péptidos/farmacología , Masculino , Hipertensión/fisiopatología , Hipertensión/tratamiento farmacológico , Hipertensión/prevención & control , Cardiomegalia/prevención & control , Cardiomegalia/fisiopatología , Cardiomegalia/metabolismo , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/patología , Estrés Oxidativo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Fibrosis , Modelos Animales de Enfermedad , Ratas , Fosforilación , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismo , Péptido Natriurético Encefálico/metabolismo , Factores de Edad , Metaloproteinasa 9 de la Matriz/metabolismo , Factor Natriurético Atrial/metabolismo , Antihipertensivos/farmacología , Remodelación Ventricular/efectos de los fármacosRESUMEN
Ghrelin is a peptide hormone whose effects are mediated by the growth hormone secretagogue receptor subtype 1a (GHS-R1a), mainly expressed in the brain but also in kidneys. The hypothesis herein raised is that GHS-R1a would be player in the renal contribution to the neurogenic hypertension pathophysiology. To investigate GHS-R1a role on renal function and hemodynamics, we used Wistar (WT) and spontaneously hypertensive rats (SHR). First, we assessed the effect of systemically injected vehicle, ghrelin, GHS-R1a antagonist PF04628935, ghrelin plus PF04628935 or GHS-R1a synthetic agonist MK-677 in WT and SHR rats housed in metabolic cages (24 h). Blood and urine samples were also analyzed. Then, we assessed the GHS-R1a contribution to the control of renal vasomotion and hemodynamics in WT and SHR. Finally, we assessed the GHS-R1a levels in brain areas, aorta, renal artery, renal cortex and medulla of WT and SHR rats using western blot. We found that ghrelin and MK-677 changed osmolarity parameters of SHR, in a GHS-R1a-dependent manner. GHS-R1a antagonism reduced the urinary Na+ and K+ and creatinine clearance in WT but not in SHR. Ghrelin reduced arterial pressure and increased renal artery conductance in SHR. GHS-R1a protein levels were decreased in the kidney and brain areas of SHR when compared to WT. Therefore, GHS-R1a role in the control of renal function and hemodynamics during neurogenic hypertension seem to be different, and this may be related to brain and kidney GHS-R1a downregulation.
Asunto(s)
Encéfalo/metabolismo , Ghrelina/administración & dosificación , Hipertensión/fisiopatología , Imidazoles/administración & dosificación , Indoles/administración & dosificación , Riñón/metabolismo , Receptores de Ghrelina/metabolismo , Compuestos de Espiro/administración & dosificación , Animales , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Regulación hacia Abajo , Ghrelina/farmacología , Hemodinámica , Hipertensión/metabolismo , Hipertensión/orina , Imidazoles/farmacología , Indoles/farmacología , Riñón/efectos de los fármacos , Riñón/fisiopatología , Pruebas de Función Renal , Masculino , Potasio/orina , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Receptores de Ghrelina/antagonistas & inhibidores , Sodio/orina , Compuestos de Espiro/farmacologíaRESUMEN
AIMS: Obesity is associated with innumerous comorbidities, including cardiovascular diseases, that occur by various mechanisms, including hyperactivation of the renin angiotensin system, oxidative stress and cardiovascular overload. Postnatal early overfeeding (PO) leads to metabolic imprinting that induces weight gain throughout life, and in this paper, we aimed to evaluate cardiovascular parameters and cardiac molecular changes due to obesity induced early in life by PO. MAIN METHODS: Male Wistar rats (120-days-old), raised in normal (NL) or small litters (SL), were submitted to cardiac assessment by transthoracic echocardiography and blood pressure evaluation. Thereafter, the hearts and aorta rings from these animals were submitted to ex-vivo isolated assays. Still, cardiac morphological and molecular analyses were performed. KEY FINDINGS: PO induced ventricular hypertrophy, raised blood pressure, increased fibrosis, and ex-vivo cardiac dysfunction in the SL group. Furthermore, SL animals presented impaired vascular relaxation and increased vascular constriction responses. Besides functional alterations, SL animals presented augmented RAB-1b and SOD-1, despite no changes in RAS receptors expression or Akt/eNOS pathway. SIGNIFICANCE: Taken together, our results consolidate the knowledge that the PO during lactation is critical for cardiometabolic programming, leading to oxidative stress and cardiac remodeling in later stages of life.