Estrogen receptors (ER) mediate functions beyond their endocrine roles, as modulation of cardiovascular, renal, and immune systems through anti-inflammatory and anti-apoptotic effects, preventing necrosis of cardiomyocytes and endothelial cells, and attenuating cardiac hypertrophy. Estradiol (E2) prevents cardiac dysfunction, increases nitric oxide synthesis, and reduces the proliferation of vascular cells, yielding protective effects, regardless of gender. Such actions are mediated by ER (ER-alpha (ERα), ER-beta (ERβ), or G protein-coupled ER (GPER)) through genomic or non-genomic pathways, which regulate cardiovascular function and prevent tissue remodeling. Despite the extensive knowledge on the cardioprotective effects of estrogen, clinical studies conducted on myocardial infarction (MI) and cardiovascular diseases still include favorable and unfavorable profiles. The purpose of this review is to provide up-to-date information regarding molecular, preclinical, and clinical aspects of cardiovascular E2 effects and ER modulation as a potential therapeutic target for the treatment of MI-induced cardiac dysfunction.
The incidence and prevalence of diabetes mellitus (DM) are increasing worldwide, and the resulting cardiac complications are the leading cause of death. Among these complications is diabetes-induced cardiomyopathy (DCM), which is the consequence of a pro-inflammatory condition, oxidative stress and fibrosis caused by hyperglycemia. Cardiac remodeling will lead to an imbalance in cell survival and death, which can promote cardiac dysfunction. Since the conventional treatment of DM generally does not address the prevention of cardiac remodeling, it is important to develop new alternatives for the treatment of cardiovascular complications induced by DM. Thus, therapy with mesenchymal stem cells has been shown to be a promising approach for the prevention of DCM because of their anti-apoptotic, anti-fibrotic and anti-inflammatory effects, which could improve cardiac function in patients with DM.
Pulmonary arterial hypertension (PAH) is characterized by the remodeling of pulmonary arteries, with an increased pulmonary arterial pressure and right ventricle (RV) overload. This work investigated the benefit of the association of human umbilical cord mesenchymal stem cells (hMSCs) with lodenafil, a phosphodiesterase-5 inhibitor, in an animal model of PAH. Male Wistar rats were exposed to hypoxia (10% O2) for three weeks plus a weekly i.p. injection of a vascular endothelial growth factor receptor inhibitor (SU5416, 20 mg/kg, SuHx). After confirmation of PAH, animals received intravenous injection of 5.105 hMSCs or vehicle, followed by oral treatment with lodenafil carbonate (10 mg/kg/day) for 14 days. The ratio between pulmonary artery acceleration time and RV ejection time reduced from 0.42 ± 0.01 (control) to 0.24 ± 0.01 in the SuHx group, which was not altered by lodenafil alone but was recovered to 0.31 ± 0.01 when administered in association with hMSCs. RV afterload was confirmed in the SuHx group with an increased RV systolic pressure (mmHg) of 52.1 ± 8.8 normalized to 29.6 ± 2.2 after treatment with the association. Treatment with hMSCs + lodenafil reversed RV hypertrophy, fibrosis and interstitial cell infiltration in the SuHx group. Combined therapy of lodenafil and hMSCs may be a strategy for PAH treatment.
Mitogen-activated protein kinase (MAPK) signaling is strongly implicated in cardiovascular remodeling in pulmonary hypertension (PH) and right ventricle (RV) failure. The effects of a newly designed p38 inhibitor, LASSBio-1824, were investigated in experimentally induced PH. Male Wistar rats were exposed to hypoxia and SU5416 (SuHx), and normoxic rats were used as controls. Oral treatment was performed for 14 days with either vehicle or LASSBio-1824 (50 mg/kg). Pulmonary vascular resistance and RV structure and function were assessed by echocardiography and catheterization. Histological, immunohistochemical and Western blot analysis of lung and RV were performed to investigate cardiovascular remodeling and inflammation. Treatment with LASSBio-1824 normalized vascular resistance by attenuating vessel muscularization and endothelial dysfunction. In the heart, treatment decreased RV systolic pressure, hypertrophy and collagen content, improving cardiac function. Protein content of TNF-α, iNOS, phosphorylated p38 and caspase-3 were reduced both in lung vessels and RV tissues after treatment and a reduced activation of transcription factor c-fos was found in cardiomyocytes of treated SuHx rats. Therefore, LASSBio-1824 represents a potential candidate for remodeling-targeted treatment of PH.
Pulmonary hypertension (PH) is characterized by extensive pulmonary vascular remodeling, leading to right ventricle (RV) hypertrophy and dysfunction. This work evaluates the hypothesis that the activation of adenosine A2A receptor (AR-A2) by LASBio-1900 could interfere with the cardiac and vascular dysfunction on monocrotaline (MCT)-induced PH in rats. After 14 days of PH induction using a single injection of MCT (60 mg/kg i.p.), twelve male Wistar rats were randomly divided in groups and treated orally either with vehicle or LASSBio-1900 (180 μmol/kg/day). Hemodynamic parameters were obtained using the echocardiography and summarized in table 1. LASSBio-1900 reduced RV hypertrophy observed in PH because the Fulton index altered from 55.4 ± 2.3 to 35.3 ± 5.9% (p<0.05). HP increased RV systolic and diastolic pressure from 19.2 ± 2.0 and 4.7 ± 1.0 to 51.5 ± 5.2 and 11.9 ± 1.3 mmHg, respectively. Ventricular dysfunction was recovered with LASSBio-1900 treatment reducing pressures to 28.4 ± 4.0 and 6.5 ± 0.8 mmHg, indicating improvement of RV dysfunction. Pulmonary arteriole (PA) muscularization was evaluated by alpha- smooth muscle actin stained and vessel medial wall area was expressed as the percentage of the portion positively stained relative to total transversal area. The increase of the wall thickness of distal PA from 61.7 ± 1.1 to 83.24 ± 1.82 % was reduced by LASSBio-1900 (75.2 ± 3.4 %). Perivascular collagen in PA was evaluated through picrosirius red staining and interstitial fibrosis was measured by obtaining the total collagen area per arteriole area. PH increased the perivascular collagen deposition in 15.1 ± 1.3% however, treatment with LASSBio-1900 reduced to 8.7 ± 1.4% (p<0.05). Intense inflammation process on PH was confirmed with the increase of iNOS expression from 4.5 ± 0.3 (control) to 19.0 ± 0.9% (p<0.05) with reduction to 8.7 ± 1.4% when treated with LASSBio-1900. In conclusion, the agonist of AR-A2, named LASSBio-1900 improved RV function and pulmonary structural alteration in PH, indicating a new alternative for treatment of PH-induced RV dysfunction.
Pulmonary hypertension (PH) is characterized by extensive pulmonary vascular remodeling, leading to right ventricle (RV) hypertrophy and dysfunction. Since Rho kinases (ROCK) play a key role in smooth muscle proliferation and cardiomyocyte hypertrophy, this work evaluated the effects of ROCK inhibition by LASSBio-2020 and LASSBio-2065 on monocrotaline (MCT)-induced PH. After single injection of MCT (60 mg/kg i.p.), male Wistar rats were randomly divided in groups and treated with vehicle, LASSBio-2020 or LASSBio-2065 (60 μmol/kg/day, i.p.). Table 1 shows summarized data. After 14 days, ROCK inhibitors reduced pulmonary vascular resistance, indicated by the ratio of pulmonary acceleration time and ejection time (PAT/TET; p< 0.05) and medial wall thickness of distal pulmonary arterioles (p< 0.05). LASSBio-2020 and LASSBio-2065 also reduced Fulton index of RV hypertrophy (p< 0.05) and RV afterload, as shown by recovery of RV cardiac output (p< 0.05) and arterial elastance (p< 0.05). ROCK inhibitors improved diastolic function since both compounds reduced RV end-diastolic pressures (RVEDP) and Tau, measured through catheterization. Therefore, ROCK inhibition by LASSBio-2020 and LASSBio-2065 reverted functional and morphological alterations in PH rats and may represent a useful alternative for management of PH-associated RV dysfunction.
Introduction: Right ventricle (RV) remodeling and vascular dysfunction are present in pulmonary arterial hypertension (PAH). Hypothesis: This work focuses on the benefits of the association of human umbilical cord mesenchymal stem cell (hMSC) with lodenafil, a PDE5 inhibitor, on PAH in rats. Methods: Experiments were in accordance with the Animal Care and Use Committee at the Federal University of Rio de Janeiro. PAH was induced in male Wistar rats by exposure to hypoxia (10% O 2 ) during 3 weeks plus i.p . injection of an antagonist of VEGF receptor (SU5416; 20 mg/kg/week). Animals were randomly divided (n=6): PAH + vehicle; PAH + lodenafil (gavage, 10 mg/kg); PAH + lodenafil + hMSC (5x10 5 , i.v.) for 14 days. Results: PAH induced the reduction of the ratio of pulmonary acceleration time and RV ejection time from 0.42 ± 0.01 to 0.24 ± 0.01, which was recovered to 0.31 ± 0.01 after treatment with lodenafil + hMSC. RV afterload confirmed by increased systolic pressure (mmHg) of 52.1 ± 8.8 (contro: 24.0 ± 3.1) was normalized to 29.6 ± 2.2 with association. Pulmonary arteries wall thickness (%) measured by immunohistochemistry for alpha-SMA was increased by HAP from 44.7 ± 1.4 to 64.2 ± 1.2 and was partial (57.7 ± 1.4) or totally recovered (47.3 ± 0.9) after treatment with lodenafil and association, respectively. Increased RV collagen fraction (%) of 7.4 ± 1.2 was induced by HAP when compared to control group (1.9 ± 0.1) and although lodenafil did not alter this parameter (6.6 ± 0.9) its association with hMSC restored to 2.7 ± 0.4. Increased RV wall thickness (mm) observed in PAH (from 0.60 ± 0.02 to 1.05 ± 0.13) recovered to 0.58 ± 0.04 after treatment with association. ERK1/2 expression evaluated by western blot analysis recovered from 0.79 ± 0.07 to 0.12 ± 0.06, which reinforced the reduction of cellular proliferation by treatment with lodenafil + hMSC. RV expression of p38 mitogen associated protein kinase was measured by stained area quantification using immunohistochemistry (%) was also increased in PAH group (from 9.4 ± 2.5 to 31.4 ± 2.2, p < 0.05) and the association of lodenafil + hMSC reduced to 11.4 ± 3.4. Conclusions: Therapy of hMSC and lodenafil improved cardiac remodeling and vascular dysfunction in SuHx-PAH rats, representing an important approach for the future treatment of PAH.
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