Description: Major depression is an important clinical factor in ventricular arrhythmia. Patients diagnosed with major depression overexpress N -methyl- d -aspartate receptors (NMDARs). Previous studies found that chronic NMDAR activation increases susceptibility to ventricular arrhythmias. We aimed to explore the mechanisms by which NMDAR activation may increase susceptibility to ventricular arrhythmias. Male rats were randomly assigned to either normal environments as control (CTL) group or 4 wk of chronic mild stress (CMS) to produce a major depression disorder (MDD) model group. After 4 wk of CMS, depression-like behaviors were measured in both groups. Varying doses (1–100 μM) of NMDA and 10 μM NMDA antagonist (MK-801) were perfused through ventricular myocytes isolated from MDD rats to measure the L-type calcium current ( I Ca-L ) and transient outward potassium current ( I to ). Structural remodeling was assessed using serial histopathology including Masson’s trichrome dye. Electrophysiological characteristics were evaluated using Langendorff perfusion. Depression-like behaviors were observed in MDD rats. MDD rats showed longer action potential durations at 90% repolarization and higher susceptibility to ventricular arrhythmias than CTL rats. MDD rats showed lower I Ca-L and I to current densities than CTL rats. Additionally, NMDA reduced both currents in a concentration-dependent manner, whereas there was no significant impact on the currents when perfused with MK-801. MDD rats exhibited significantly more fibrosis areas in heart tissue and reduced expression of Kv4.2, Kv4.3, and Cav1.2. We observed that acute NMDAR activation led to downregulation of potassium and L-type calcium currents in a rat model of depression, which may be the mechanism underlying ventricular arrhythmia promotion by depression.

Description: The alveolar epithelium is composed of type I cells covering most of the gas-blood exchange surface and type II cells secreting surfactant that lowers surface tension of alveoli to prevent alveolar collapse. Here, we have identified a subgroup of type II cells expressing a higher level of cell surface molecule CD44 (CD44 high type II cells) that composed ~3% of total type II cells in 5–10-wk-old mice. These cells were preferentially apposed to lung capillaries. They displayed a higher proliferation rate and augmented differentiation capacity into type I cells and the ability to form alveolar organoids compared with CD44 low type II cells. Moreover, in aged mice, 18–24 mo old, the percentage of CD44 high type II cells among all type II cells was increased, but these cells showed decreased progenitor properties. Thus CD44 high type II cells likely represent a type II cell subpopulation important for constitutive regulation of alveolar homeostasis.

Description: CC chemokine ligand-2 (CCL2)/monocyte chemoattractant protein (MCP)-1 expression is upregulated during pulmonary inflammation, and the CCL2-CCR2 axis plays a critical role in leukocyte recruitment and promotion of host defense against infection. The role of CCL2 in mediating macrophage subpopulations in the pathobiology of noninfectious lung injury is unknown. The goal of this study was to examine the role of CCL2 in noninfectious acute lung injury. Our results show that lung-specific overexpression of CCL2 protected mice from bleomycin-induced lung injury, characterized by significantly reduced mortality, reduced neutrophil accumulation, and decreased accumulation of the inflammatory mediators IL-6, CXCL2 (macrophage inflammatory protein-2), and CXCL1 (keratinocyte-derived chemokine). There were dramatic increases in the recruitment of myosin heavy chain (MHC) II IA/IE int CD11c int cells, exudative macrophages, and dendritic cells in Ccl2 transgenic mouse lungs both at baseline and after bleomycin treatment compared with levels in wild-type mice. We further demonstrated that MHCII IA/IE int CD11c int cells engulfed apoptotic cells during acute lung injury. Our data suggested a previously undiscovered role for MHCII IA/IE int CD11c int cells in apoptotic cell clearance and inflammation resolution.

Description: There is a global epidemic of obesity, and obesity is known to inhibit AMP-activated protein kinase (AMPK) activity and impairs myogenesis. Myogenin mediates the fusion of myoblasts into myotubes, a critical step in myogenesis. We observed that inhibition of AMPKα1 downregulates myogenin expression and myogenesis, but the underlying mechanisms are unclear. We postulated that AMPK regulates myogenin expression through phosphorlytion of histone deacetylase 5 (HDAC5). In C2C12 cells, HDAC5 knockdown increased while HDAC5 stablization by MC1568 reduced myogenin expression. Consistently, using luciferase assay, we observed that myogenin promoter activity was negatively regulated by HDAC5. Using RNA interference and primary myoblasts prepared from wild-type and AMPKα1 knockout mice, we further demonstrate that AMPKα1 regulates HDAC5 phosphorylation at Ser 259 and 498. Mutation of these two Ser to Ala in HDAC5 abolished the regulatory role of AMPKα1 on myogenin expression, clearly showing the necessity of these phosphorylation sites in mediating myogenin expression. In aggregate, these data show that AMPK inhibition downregulates myogenin transcription and myogenesis through phosphorylation of HDAC5, mediated mainly by AMPKα1. These data demonstrate that AMPK is a key molecular target for promoting myogenesis and muscular regeneration. Because drugs activating AMPK activity, such as metformin, are widely available, our finding has critical clinical implications to ensure proper muscle development and regeneration in obese subjects and under other pathophysiological conditions where AMPK activity is attenuated.