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Aims: Pulmonary arterial hypertension (PAH) is a disease characterized by an increase in pulmonary vascular resistance and right ventricular (RV) failure. We aimed to determine the effects of human mesenchymal stem cell (hMSC) therapy in a SU5416/hypoxia (SuH) mice model of PAH.Methods and Results: C57BL/6 mice (20–25 g) were exposure to 4 weeks of hypoxia combined vascular endothelial growth factor receptor antagonism (20 mg/kg SU5416; weekly s.c. injections; PAH mice). Control mice were housed in room air. Following 2 weeks of SuH exposure, we injected 5 × 105 hMSCs cells suspended in 50 μL of vehicle (0.6 U/mL DNaseI in PBS) through intravenous injection in the caudal vein. PAH mice were treated only with vehicle. Ratio between pulmonary artery acceleration time and RV ejection time (PAAT/RVET), measure by echocardiography, was significantly reduced in the PAH mice, compared with controls, and therapy with hMSCs normalized this. Significant muscularization of the PA was observed in the PAH mice and hMSC reduced the number of fully muscularized vessels. RV free wall thickness was higher in PAH animals than in the controls, and a single injection of hMSCs reversed RV hypertrophy. Levels of markers of exacerbated apoptosis, tissue inflammation and damage, cell proliferation and oxidative stress were significantly greater in both lungs and RV tissues from PAH group, compared to controls. hMSC injection in PAH animals normalized the expression of these molecules which are involved with PAH and RV dysfunction development and the state of chronicity.Conclusion: These results indicate that hMSCs therapy represents a novel strategy for the treatment of PAH in the future.

Pulmonary hypertension (PH) is a disease of women (female-to-male ratio 4:1), and is associated with cardiac and skeletal muscle dysfunction. Herein, the activation of a new estrogen receptor (GPER) by the agonist G1 was evaluated in oophorectomized rats with monocrotaline (MCT)-induced PH. Depletion of estrogen was induced by bilateral oophorectomy (OVX) in Wistar rats. Experimental groups included SHAM or OVX rats that received a single intraperitoneal injection of MCT (60 mg/kg) for PH induction. Animals received s.c. injection of either vehicle or G1, a GPER agonist, (400 µg/kg/day) for 14 days after the onset of disease. Rats with PH exhibited exercise intolerance and cardiopulmonary alterations, including reduced pulmonary artery flow, biventricular remodeling, and left ventricular systolic and diastolic dysfunction. The magnitude of these PH-induced changes was significantly greater in OVX versus SHAM rats. G1 treatment reversed both cardiac and skeletal muscle functional aberrations caused by PH in OVX rats. G1 reversed PH-related cardiopulmonary dysfunction and exercise intolerance in female rats, a finding that may have important implications for the ongoing clinical evaluation of new drugs for the treatment of the disease in females after the loss of endogenous estrogens.

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It is known the association between malnutrition and hypertension in the adult life. The aim of this study was to determine the consequences of the brazilian regional basic diet (RBD) submitted chronically to Wistar rats in the function and in the intracellular Ca2+ homeostasis of the heart. After weaning, the rats were fed with RBD and conventional diet for 10 weeks (n=10 each). The rats were subjected to echocardiography. A cohort of 5 hearts was isolated, perfused with Krebs buffer in the presence or absence of isoproterenol (ISP, from 0.3 to 1000 nM) by the Langendorff method. The microssomal fractions of the ventricles were obtained to measure the Ca2+‐ATPase activities. Ecocardiographic analysis showed a decrease in the cardiac output (53%), ejection fraction (71%), stroke volume (48%), and left diastolic ventricular diameter (22%) in the RBD. The left ventricular developed pressure was decreased in the RBD (34%). Furthermore, the contractility (+LVdP/dt) and relaxation (−LVdP/dt) in the presence of ISP are disrupted. The lung weight/body weight ratio were increased in 75%. We observed that the total Ca2+‐ATPase activity was two times higher in the RBD; due to a decrease in SERCA and an increase in the PMCA activities. Our data indicate that chronic malnutrition unbalances the SERCA and PMCA activities that could affect the heart hemodynamic.

Introduction: Prevention of cardiac remodeling induced by myocardial infarction (MI) is of great importance because it is one of the factors for the development of heart failure (HF). Thus, LASSBio-1027 was tested in acute model of MI due to its vasodilatory and anti-proliferative profile through the activation of adenosine A 2A and A 3 receptors.Methods: Protocols were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. MI was induced in male Wistar rats (180-200 g) which were subjected to ligation of the anterior descending coronary artery under isoflorane anesthesia (3% v/v). Animals were randomly divided into groups treated orally (gavage) with either vehicle or LASSBio-1027 (30 and 70 umol/kg) for 7 days. All groups underwent echocardiographic analysis and anterior wall thickness (AWTd) during diastole; mitral flow using the ratio between early transmitral filling velocity (E) and tissue doppler (e , ) were determined. The border of infarcted area was used to evaluate interstitial cells and expression of alpha-SMA. Expression of TNF-alpha, SERCA2, p-ERK-1/2 and ERK-1/2 were also investigated. Results: MI reduced AWTd from 1.24 ± 0.17 to 0.42 ± 0.02 mm (P<0.01) which was recovered after treatment with LASSBio-1027. Mitral flow was increased from 22.9 ± 1.6 to 37.0 ± 3.6 (P<0.01) after experimental MI and reduced with LASSBio-1027. The ejection fraction in MI group was 36.6 ± 2.0% which was increased to 46.99 ± 7.40% after treatment (P<0.05). An increase of collagen deposition was observed in MI group of 33.35 ± 5.74% and treatment with LASSBio-1027 (70 µmol/kg) reduced to 14.50 ± 0.32% (P<0.05). LASSBio-1027 reduced interstitial cells from 275.5 ± 49.13 (MI group) to 110.1 ±17.09 (P<0.05). It was observed an increased alpha-SMA expression in the MI group with 36.83 ± 2.89% and a reduction after treatment with LASSBio-1027, 6.28 ± 4.12% and 14.01 ± 4.31%, for 30 and 70 µmol/kg. MI increased the expression of TNF-alpha, p-ERK1-2/ERK1-2 and SERCA2 in comparison to Sham. LASSBio-1027 at 30 μmol/kg recovered the expression of all proteins to control values. Conclusion: LASSBio-1027 prevented the development of HF by improving cardiac remodeling after acute MI.