ABSTRACT
BACKGROUND AND AIMS: Agonists of peroxisome proliferator-activated receptor gamma (Pparγ) have been demonstrated to reduce the risk of myocardial infarction (MI) in clinical trials and animal experiments. However, the cellular and molecular mechanisms are not completely understood. We aimed to reveal the functions of myeloid Pparγ in MI and explore the potential mechanisms in this study. METHODS: Myeloid Pparγ knockout (MPGKO) mice (nâ¯=â¯12) and control mice (nâ¯=â¯8) underwent coronary artery ligation to induce MI. Another cohort of MPGKO mice and control mice underwent coronary artery ligation and were then treated with IgG or neutralizing antibodies against interleukin (IL)-1ß. Infarct size was determined by TTC staining and cardiac function was measured using echocardiography. Conditioned media from GW9662- or vehicle-treated macrophages were used to treat H9C2 cardiomyocyte cell line. Gene expression was analyzed using quantitative PCR. Reactive oxygen species were measured using flow cytometry. RESULTS: Myeloid Pparγ deficiency significantly increased myocardial infarct size. Cardiac hypertrophy was also exacerbated in MPGKO mice, with upregulation of ß-myosin heavy chain (Mhc) and brain natriuretic peptide (Bnp) and downregulation of α-Mhc in the non-infarcted zone. Conditioned media from GW9662-treated macrophages increased expression of ß-Mhc and Bnp in H9C2 cells. Echocardiographic measurements showed that MPGKO mice had worsen cardiac dysfunction after MI. Myeloid Pparγ deficiency increased gene expression of NADPH oxidase subunits (Nox2 and Nox4) in the non-infarcted zone after MI. Conditioned media from GW9662-treated macrophages increased reactive oxygen species in H9C2 cells. Expression of inflammatory genes such as IL-1ß and IL-6 was upregulated in the non-infarcted zone of MPGKO mice after MI. With the injection of neutralizing antibodies against IL-1ß, control mice and MPGKO mice had comparable cardiac function and expression of inflammatory genes after MI. CONCLUSIONS: Myeloid Pparγ deficiency exacerbates MI, likely through increased oxidative stress and cardiac inflammation.
Subject(s)
Macrophages, Peritoneal/metabolism , Myocardial Infarction/metabolism , Myocytes, Cardiac/metabolism , PPAR gamma/deficiency , Animals , Cell Line , Disease Models, Animal , Disease Progression , Genetic Predisposition to Disease , Hypertrophy, Left Ventricular/genetics , Hypertrophy, Left Ventricular/metabolism , Hypertrophy, Left Ventricular/pathology , Hypertrophy, Left Ventricular/physiopathology , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Mice, Knockout , Myocardial Infarction/genetics , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocytes, Cardiac/pathology , Myosin Heavy Chains/genetics , Myosin Heavy Chains/metabolism , NADPH Oxidase 2/genetics , NADPH Oxidase 2/metabolism , NADPH Oxidase 4/genetics , NADPH Oxidase 4/metabolism , Natriuretic Peptide, Brain/genetics , Natriuretic Peptide, Brain/metabolism , Oxidative Stress , PPAR gamma/genetics , Phenotype , Signal Transduction , Time Factors , Ventricular Function, Left , Ventricular RemodelingABSTRACT
In order to explore the ecological factors affecting the growth of Astragalu smembranaceus var. mongholicus, we investigated the resource distribution, habitat characteristics and growth conditions of wild and cultivated A. membranaceus var. mongholicus by fixed-plot observation, survey method, and literature. These data were analyzed by traditional Chinese medicine GIS-2 (TCMGS-2) to obtain the most suitable areas of A. membranaceus var. mongholicus within Inner Mongolia. The results showed that the production areas of cultivated A. membranaceus var. mongholicus were mainly located in Wuchuan County, Guyang County and other 15 counties, which were cha-racterized by the altitude higher than 1000 m, with soil type of sand, gravel and calcareous clay. The wild A. membranaceus var. mongholicus was distributed mainly in the eastern Inner Mongolia and germinated in sunny place, which preferred to the cold dry climate and sandy loam soil or gra-vel but avoided damp heavy clay soils. There are 43 counties of 94460.30 km2 for wild A. membranaceus var. mongholicus, and 32 counties of 76013.93 km2 for cultivated one within Inner Mongolia, with a similarity coefficient of ecological factors greater than 95%.
Subject(s)
Astragalus propinquus/growth & development , Climate , Ecosystem , China , Germination , Plants, Medicinal/growth & development , SoilABSTRACT
Principal component analysis (PCA) and correlation analysis (CA) were applied to analyze the correlation of the main chemical components in Astragalus membranaceus var. mongholicus and ecological factors. The results showed that the contents of astragaloside, campanulin, ononin, kaempferol and astragalus polysaccharides (APS) of A. membranaceus var. mongholicus produced. in Shanxi were significantly higher than in Inner Mongolia and Gansu. The main climatic factors for affecting the contents of chemical ingredients in A. membranaceus var. mongholicus were annual average relative humidity, sunshine hours and average July temperature. Calcium was the main factor in the soil affecting the chemical ingredient contents, and calcium was negatively correlated with the contents of calycosin glycosides, kaempferol, ononin, quercetin and APS in A. membranaceus var. mongholicus within a certain range.
Subject(s)
Astragalus propinquus/chemistry , Climate , Calcium/analysis , China , Glucosides/analysis , Isoflavones/analysis , Kaempferols/analysis , Polysaccharides/analysis , Quercetin/analysis , Soil/chemistryABSTRACT
Mineralocorticoid receptor (MR) blockade has been shown to suppress cardiac hypertrophy and remodeling in animal models of pressure overload (POL). This study aims to determine whether MR deficiency in myeloid cells modulates aortic constriction-induced cardiovascular injuries. Myeloid MR knockout (MMRKO) mice and littermate control mice were subjected to abdominal aortic constriction (AAC) or sham operation. We found that AAC-induced cardiac hypertrophy and fibrosis were significantly attenuated in MMRKO mice. Expression of genes important in generating reactive oxygen species was decreased in MMRKO mice, while that of manganese superoxide dismutase increased. Furthermore, expression of genes important in cardiac metabolism was increased in MMRKO hearts. Macrophage infiltration in the heart was inhibited and expression of inflammatory genes was decreased in MMRKO mice. In addition, aortic fibrosis and inflammation were attenuated in MMRKO mice. Taken together, our data indicated that MR deficiency in myeloid cells effectively attenuated aortic constriction-induced cardiac hypertrophy and fibrosis, as well as aortic fibrosis and inflammation.
Subject(s)
Aorta, Abdominal/metabolism , Hypertrophy, Left Ventricular/pathology , Receptors, Mineralocorticoid/genetics , Animals , Aorta, Abdominal/pathology , Constriction, Pathologic/metabolism , Constriction, Pathologic/pathology , Gene Expression Regulation , Hypertrophy, Left Ventricular/etiology , Hypertrophy, Left Ventricular/genetics , Hypertrophy, Left Ventricular/metabolism , Macrophages/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Reactive Oxygen Species/metabolism , Receptors, Mineralocorticoid/metabolismABSTRACT
Neuronostatin is a recently discovered endogenous bioactive peptide that is encoded by pro-mRNA of somatostatin. In the present study, we investigated the effect of neuronostatin on mood regulation in the forced swim test of mice. Our results showed intracerebroventricular (i.c.v.) administration of neuronostatin produced an increase in the immobility time, suggesting that neuronostatin induced depression-like effect. In order to rule out the possibility that neuronostatin had increased immobility time by a non-specific reduction in general activity, the effect of neuronostatin on locomotor activity was examined. Neuronostatin had no influence on locomotor activity in mice. In addition, the depression-like effect of neuronostatin was completely reversed by melanocortin 3/4 receptor antagonist SHU9119 or GABAA receptor antagonist bicuculline, but not by opioid receptor antagonist naloxone. These data suggested that the depression-like effect induced by i.c.v. administered neuronostatin was dependent upon the central melanocortin system and GABAA receptor. In conclusion, the results of this study report that neuronostatin induces depression-like effect. These findings reveal that neuronostatin is a new neuropeptide with an important role in regulating depressive behavior.
Subject(s)
Affect/drug effects , Depression/chemically induced , Peptide Hormones/administration & dosage , Peptide Hormones/pharmacology , Animals , Bicuculline/administration & dosage , Bicuculline/pharmacology , GABA-A Receptor Antagonists/pharmacology , Infusions, Intraventricular , Male , Melanocyte-Stimulating Hormones/pharmacology , Mice , Motor Activity , Naloxone/administration & dosage , Naloxone/pharmacology , Narcotic Antagonists , Peptide Hormones/chemical synthesis , Receptor, Melanocortin, Type 3/antagonists & inhibitors , Receptors, GABA-A/metabolism , Solid-Phase Synthesis Techniques , Swimming/physiology , Time FactorsABSTRACT
In the present study, we investigated the antidepressive activity of opiorphin with central administration in the forced swim test in mice. Intracerebroventricular (i.c.v.) administration of opiorphin (1-6 µg/mouse) dose-dependently decreased the immobility time, which was reversed by nonselective opioid receptor antagonist naloxone, δ-selective naltrindole and µ-selective ß-FNA. The data suggested that central administration of opiorphin produced an antidepressant-like effect by activating both µ and δ opioid receptors indirectly. In order to eliminate the possibility of a false-positive result in the forced swim test, locomotor activity was checked in both non-habituated and habituated mice. Opiorphin had no influence on non-habituated mice, though had weak effect on habituated mice. In addition, mice treated with opiorphin did not display any convulsive behaviors.
