Cardiac fibroblast activation during myocardial infarction wound healing: Fibroblast polarization after MI.

Cardiac wound healing after myocardial infarction (MI) evolves from pro-inflammatory to anti-inflammatory to reparative responses, and the cardiac fibroblast is a central player during the entire transition. The fibroblast mirrors changes seen in the left ventricle infarct by undergoing a continuum of polarization phenotypes that follow pro-inflammatory, anti-inflammatory, and pro-scar producing profiles. The development of each phenotype transition is contingent upon the MI environment into which the fibroblast enters. In this mini-review, we summarize our current knowledge regarding cardiac fibroblast activation during MI and highlight key areas where gaps remain.

Neuroprotective and neurotoxic outcomes of androgens and estrogens in an oxidative stress environment.

BACKGROUND: The role of sex hormones on cellular function is unclear. Studies show androgens and estrogens are protective in the CNS, whereas other studies found no effects or damaging effects. Furthermore, sex differences have been observed in multiple oxidative stress-associated CNS disorders, such as Alzheimer's disease, depression, and Parkinson's disease. The goal of this study is to examine the relationship between sex hormones (i.e., androgens and estrogens) and oxidative stress on cell viability. METHODS: N27 and PC12 neuronal and C6 glial phenotypic cell lines were used. N27 cells are female rat derived, whereas PC12 cells and C6 cells are male rat derived. These cells express estrogen receptors and the membrane-associated androgen receptor variant, AR45, but not the full-length androgen receptor. N27, PC12, and C6 cells were exposed to sex hormones either before or after an oxidative stressor to examine neuroprotective and neurotoxic properties, respectively. Estrogen receptor and androgen receptor inhibitors were used to determine the mechanisms mediating hormone-oxidative stress interactions on cell viability. Since the presence of AR45 in the human brain tissue was unknown, we examined the postmortem brain tissue from men and women for AR45 protein expression. RESULTS: Neither androgens nor estrogens were protective against subsequent oxidative stress insults in glial cells. However, these hormones exhibited neuroprotective properties in neuronal N27 and PC12 cells via the estrogen receptor. Interestingly, a window of opportunity exists for sex hormone neuroprotection, wherein temporary hormone deprivation blocked neuroprotection by sex hormones. However, if sex hormones are applied following an oxidative stressor, they exacerbated oxidative stress-induced cell loss in neuronal and glial cells. CONCLUSIONS: Sex hormone action on cell viability is dependent on the cellular environment. In healthy neuronal cells, sex hormones are protective against oxidative stress insults via the estrogen receptor, regardless of sex chromosome complement (XX, XY). However, in unhealthy (e.g., high oxidative stress) cells, sex hormones exacerbated oxidative stress-induced cell loss, regardless of cell type or sex chromosome complement. The non-genomic AR45 receptor, which is present in humans, mediated androgen's damaging effects, but it is unknown which receptor mediated estrogen's damaging effects. These differential effects of sex hormones that are dependent on the cellular environment, receptor profile, and cell type may mediate the observed sex differences in oxidative stress-associated CNS disorders.

Understanding the mechanisms that determine extracellular matrix remodeling in the infarcted myocardium.

Myocardial Infarction (MI) initiates a series of wound healing events that begins with up-regulation of an inflammatory response and culminates in scar formation. The extracellular matrix (ECM) is intricately involved in all stages from initial break down of existing ECM to synthesis of new ECM to form the scar. This review will summarize our current knowledge on the processes involved in ECM remodeling after MI and identify the gaps that still need to be filled.

NADPH Oxidase Mediates Membrane Androgen Receptor-Induced Neurodegeneration.

Oxidative stress (OS) is a common characteristic of several neurodegenerative disorders, including Parkinson disease (PD). PD is more prevalent in men than in women, indicating the possible involvement of androgens. Androgens can have either neuroprotective or neurodamaging effects, depending on the presence of OS. Specifically, in an OS environment, androgens via a membrane-associated androgen receptor (mAR) exacerbate OS-induced damage. To investigate the role of androgens on OS signaling and neurodegeneration, the effects of testosterone and androgen receptor activation on the major OS signaling cascades, the reduced form of NAD phosphate (NADPH) oxidase (NOX)1 and NOX2 and the Gαq/inositol trisphosphate receptor (InsP3R), were examined. To create an OS environment, an immortalized neuronal cell line was exposed to H2O2 prior to cell-permeable/cell-impermeable androgens. Different inhibitors were used to examine the role of G proteins, mAR, InsP3R, and NOX1/2 on OS generation and cell viability. Both testosterone and DHT/3-O-carboxymethyloxime (DHT)-BSA increased H2O2-induced OS and cell death, indicating the involvement of an mAR. Furthermore, classical AR antagonists did not block testosterone's negative effects in an OS environment. Because there are no known antagonists specific for mARs, an AR protein degrader, ASC-J9, was used to block mAR action. ASC-J9 blocked testosterone's negative effects. To determine OS-related signaling mediated by mAR, this study examined NOX1, NOX2, Gαq. NOX1, NOX2, and the Gαq complex with mAR. Only NOX inhibition blocked testosterone-induced cell loss and OS. No effects of blocking either Gαq or G protein activation were observed on testosterone's negative effects. These results indicate that androgen-induced OS is via the mAR-NOX complex and not the mAR-Gαq complex.