angiotensin-i and Hypertrophy--Right-Ventricular

Tsantan Sumtang, which consists of Choerospondias axillaris (Roxb.) Burtt et Hill, Myristica fragrans Houtt and Santalum album L, is a traditional and common prescription of Tibetan medicine. Tsantan Sumtang originates from Four Tantra with properties of nourishing heart and has been used as a folk medicine for cardiovascular diseases and heart failure in Qinghai, Tibet and Inner Mongolia. Our previous studies found that Tsantan Sumtang showed beneficial effects on right ventricular structure in hypoxia rats, while the underling mechanism remains unclear.. To elucidate the underlying mechanisms of Tsantan Sumtang attenuated right ventricular (RV) remodeling and fibrosis of chronic hypoxia-induced pulmonary arterial hypertension (HPAH) rats.. Our results showed that RVHI, RV/TL and RVSP were significantly increased in HPAH rat. Furthermore, levels of collagen I, collagen III and hydroxyproline were up-regulated in RV tissue under hypoxia. We found that RV hypertrophy and fibrosis were associated with increased expression of ACE, AngII, AT1R as well as decreased expression of ACE2, Ang1-7 and Mas. RV remodeling and fibrosis were attenuated after Tsantan Sumtang administration by up-regulating ACE2 and Mas level as well as down-regulating ACE, AngII and AT1R levels in RV tissue. 35 constituents in Tsantan Sumtang were identified.. Tsantan Sumtang attenuated RV remodeling and fibrosis in rat exposed to chronic hypoxia. The pharmacological effect of Tsantan Sumtang was based on equilibrating ACE-AngII-AT1R and ACE2-Ang1-7-Mas axis of RV tissue in HPAH rat.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrosis; Hypertrophy, Right Ventricular; Hypoxia; Male; Medicine, Tibetan Traditional; Peptide Fragments; Peptidyl-Dipeptidase A; Plant Preparations; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Ventricular Remodeling

A long-term imbalance between pro- and anti-inflammatory mediators leads to airway remodelling, which is strongly correlated to most of the symptoms, severity and progression of chronic lung inflammation. The Angiotensin-(1-7) [Ang-(1-7)]/Mas receptor axis of the renin-angiotensin system is associated with attenuation of acute and chronic inflammatory processes. In this study, we investigated the effects of Ang-(1-7) treatment in a model of chronic allergic lung inflammation.. Mice were sensitized to ovalbumin (OVA; 4 injections over 42 days, 14 days apart) and were challenged three times per week (days 21-46). These mice received Ang-(1-7) (1 μg·h(-1) , s.c.) by osmotic mini-pumps, for the last 28 days. Histology and morphometric analysis were performed in left lung and right ventricle. Airway responsiveness to methacholine, analysis of Ang-(1-7) levels (RIA), collagen I and III (qRT-PCR), ERK1/2 and JNK (Western blotting), IgE (elisa), cytokines and chemokines (elisa multiplex), and immunohistochemistry for Mas receptors were performed.. Infusion of Ang-(1-7) in OVA-sensitized and challenged mice decreased inflammatory cell infiltration and collagen deposition in the airways and lung parenchyma, and prevented bronchial hyperresponsiveness. These effects were accompanied by decreased IgE and ERK1/2 phosphorylation, and decreased pro-inflammatory cytokines. Mas receptors were detected in the epithelium and bronchial smooth muscle, suggesting a site in the lung for the beneficial actions of Ang-(1-7).. Ang-(1-7) exerted beneficial attenuation of three major features of chronic asthma: lung inflammation, airway remodelling and hyperresponsiveness. Our results support an important protective role of Ang-(1-7) in lung inflammation.

Topics: Airway Remodeling; Angiotensin I; Animals; Anti-Inflammatory Agents; Bronchial Hyperreactivity; Bronchoconstriction; Collagen; Cytokines; Disease Models, Animal; Hypertrophy, Right Ventricular; Immunoglobulin E; Inflammation Mediators; Lung; Male; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Ovalbumin; Peptide Fragments; Phosphorylation; Pneumonia; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Respiratory Hypersensitivity; Signal Transduction

Angiotensin-converting enzyme 2 (ACE2), an ACE homolog, hydrolyzes angiotensin II and opposes its actions, and plays a protective role in the pathogenesis of pulmonary arterial hypertension (PAH). However, the underlying mechanisms involved in the effect of ACE2 on PAH are still uncertain. In this study, we observed the effects of ACE2 activation on endothelial dysfunction and vascular remodeling in the development of severe PAH in rats.. Severe PAH was induced by monocrotaline injection 1 week following left pneumonectomy, and ACE2 was activated by continuous injection of resorcinolnaphthalein. The PAH-related hemodynamics, pathological changes, and endothelium-dependent vasorelaxation were examined to assess the effects of ACE2 activation. In addition, the changes of the main components of the renin-angiotensin system were identified by ELISA or Western blotting.. Severe PAH was established at 3 weeks and was characterized by high pulmonary arterial pressure (45 mmHg), significant right ventricular hypertrophy, neointimal occlusive lesions, and impaired endothelium-dependent relaxation in pulmonary arteries. Coadministration of resorcinolnaphthalein reduced pulmonary arterial pressure, right ventricular hypertrophy, and neointimal formation and shifted the endothelial-dependent responses toward values measured in normal rats. Theses changes were associated with an increase in ACE2 and angiotensin-(1-7) levels and a decrease in ACE and angiotensin II levels, in addition to a decrease in the ACE/ACE2 ratio and the angiotensin II/angiotensin-(1-7) ratio. The beneficial effects of resorcinolnaphthalein were abolished by A-779.. These findings suggested that ACE2 activation by resorcinolnaphthalein improved endothelial function and suppressed neointimal formation in the prevention of severe PAH by the mechanism of mediating the levels of the components of the renin-angiotensin system.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Arterial Pressure; Cytoprotection; Disease Models, Animal; Endothelium, Vascular; Enzyme Activation; Enzyme Activators; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Naphthalenes; Neointima; Peptide Fragments; Peptidyl-Dipeptidase A; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Resorcinols; Severity of Illness Index; Time Factors; Vasodilation

Stimulation of MAS oncogene receptor (MAS) or angiotensin (Ang) receptor type 2 (AT2) may be novel therapeutic options for neonatal chronic lung disease (CLD) by counterbalancing the adverse effects of the potent vasoconstrictor angiotensin II, consisting of arterial hypertension (PAH)-induced right ventricular hypertrophy (RVH) and pulmonary inflammation. We determined the cardiopulmonary effects in neonatal rats with CLD of daily treatment during continuous exposure to 100% oxygen for 10 days with specific ligands for MAS [cyclic Ang-(1-7); 10-50 μg·kg(-1)·day(-1)] and AT2 [dKcAng-(1-7); 5-20 μg·kg(-1)·day(-1)]. Parameters investigated included lung and heart histopathology, fibrin deposition, vascular leakage, and differential mRNA expression in the lungs of key genes involved in the renin-angiotensin system, inflammation, coagulation, and alveolar development. We investigated the role of nitric oxide synthase inhibition with N(ω)-nitro-l-arginine methyl ester (25 mg·kg(-1)·day(-1)) during AT2 agonist treatment. Prophylactic treatment with agonists for MAS or AT2 for 10 days diminished cardiopulmonary injury by reducing alveolar septum thickness and medial wall thickness of small arterioles and preventing RVH. Both agonists attenuated the pulmonary influx of inflammatory cells, including macrophages (via AT2) and neutrophils (via MAS) but did not reduce alveolar enlargement and vascular alveolar leakage. The AT2 agonist attenuated hyperoxia-induced fibrin deposition. In conclusion, stimulation of MAS or AT2 attenuates cardiopulmonary injury by reducing pulmonary inflammation and preventing PAH-induced RVH but does not affect alveolar and vascular development in neonatal rats with experimental CLD. The beneficial effects of AT2 activation on experimental CLD were mediated via a NOS-independent mechanism.

Topics: Angiotensin I; Animals; Animals, Newborn; Apoptosis; Blotting, Western; Bronchoalveolar Lavage; Cell Proliferation; Hyperoxia; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Lung Injury; Male; Oxygen; Peptide Fragments; Pneumonia; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

AVE 0991 (AVE) is a non-peptide compound, mimic of the angiotensin (Ang)-(1-7) actions in many tissues and pathophysiological states. Here, we have investigated the effect of AVE on pulmonary remodelling in a murine model of ovalbumin (OVA)-induced chronic allergic lung inflammation.. We used BALB/c mice (6-8 weeks old) and induced chronic allergic lung inflammation by OVA sensitization (20 μg·mouse(-1) , i.p., four times, 14 days apart) and OVA challenge (1%, nebulised during 30 min, three times per·week, for 4 weeks). Control and AVE groups were given saline i.p and challenged with saline. AVE treatment (1 mg·kg(-1) ·per day, s.c.) or saline (100 μL·kg(-1) ·per day, s.c.) was given during the challenge period. Mice were anaesthetized 72 h after the last challenge and blood and lungs collected. In some animals, primary bronchi were isolated to test contractile responses. Cytokines were evaluated in bronchoalveolar lavage (BAL) and lung homogenates.. Treatment with AVE of OVA sensitised and challenged mice attenuated the altered contractile response to carbachol in bronchial rings and reversed the increased airway wall and pulmonary vasculature thickness and right ventricular hypertrophy. Furthermore, AVE reduced IL-5 and increased IL-10 levels in the BAL, accompanied by decreased Ang II levels in lungs.. AVE treatment prevented pulmonary remodelling, inflammation and right ventricular hypertrophy in OVA mice, suggesting that Ang-(1-7) receptor agonists are a new possibility for the treatment of pulmonary remodelling induced by chronic asthma.

Topics: Airway Remodeling; Angiotensin I; Angiotensin II; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Chronic Disease; Cytokines; Disease Models, Animal; Hypertrophy, Right Ventricular; Imidazoles; Lung; Male; Mice; Mice, Inbred BALB C; Molecular Mimicry; Ovalbumin; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Pulmonary Artery; Pulmonary Veins; Receptors, G-Protein-Coupled; Time Factors

We investigated the endogenous production of apelin and the cardiac and pulmonary effects of its chronic administration in monocrotaline (MCT)-induced pulmonary hypertension (PH). Male Wistar rats were injected with MCT (60 mg/kg sc) or vehicle (day 0). One week later, these animals were randomly treated during 17 days with pyroglutamylated apelin-13 (Pyr-AP13; 200 microg*kg(-1)*day(-1) ip) or a similar volume of saline, resulting in four groups: sham (n = 11), sham-AP (n = 11), MCT (n = 16), and MCT-AP (n = 13). On day 25, right ventricular (RV) and left ventricular (LV) hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis. When compared with sham, the MCT group presented a significant increase of RV mass (166 +/- 38%), diameter of cardiomyocyte (40 +/- 10%), myocardial fibrosis (95 +/- 20%), peak systolic pressure (99 +/- 22%), peak rate of ventricular pressure rise (dP/dt(max); 74 +/- 24%), peak rate of ventricular pressure decline (dP/dt(min); 73 +/- 19%), and time constant tau (55 +/- 16%). In these animals, RV expression of apelin (-73 +/- 10%) and its receptor APJ (-61 +/- 20%) was downregulated, whereas mRNA expression of type B natriuretic peptide (9,606 +/- 713%), angiotensinogen (191 +/- 147%), endothelin-1 (RV, 497 +/- 156%; and LV, 799 +/- 309%), plasmatic levels of apelin (104 +/- 48%), and angiotensin 1-7 (161 +/- 151%) were increased. Chronic treatment with Pyr-AP13 significantly attenuated or normalized these changes, preventing apelin-APJ mRNA downregulation and PH-induced neurohumoral activation of several vasoconstrictors, which exacerbates apelin-APJ vasodilator effects. Therefore, apelin delayed the progression of RV hypertrophy and diastolic dysfunction. Together, these observations suggest that the apelin-APJ system may play an important role in the pathophysiology of PH, representing a potential therapeutic target since it significantly attenuates RV overload and PH-induced neurohumoral activation.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Apelin; Apelin Receptors; Carrier Proteins; Endothelin-1; Gene Expression Profiling; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Intercellular Signaling Peptides and Proteins; Male; Monocrotaline; Myocardium; Peptide Fragments; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; RNA, Messenger; Ventricular Function, Right