Myeloid peroxisome proliferator-activated receptor gamma deficiency aggravates myocardial infarction in mice.

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 (n = 12) and control mice (n = 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.

Myeloid mineralocorticoid receptor deficiency inhibits aortic constriction-induced cardiac hypertrophy in mice.

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.

Intracerebroventricular administration of neuronostatin induces depression-like effect in forced swim test of mice.

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.