Highlights► The p38 MAPK signaling pathway regulates cardiac remodeling. ► Human cardiac fibroblasts express the α, γ and δ subtypes of p38 MAPK. ► IL-1 selectively stimulates p38α and p38γ activation. ► p38α is important for IL-1-induced IL-6 and MMP-3 expression in cardiac fibroblasts.

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Oestrogen influences autonomic function via actions at classical nuclear oestrogen receptors α and β in the brain, and recent evidence suggests the orphan G protein-coupled receptor GPR30 may also function as a cytoplasmic oestrogen receptor. We investigated the expression of GPR30 in female rat brains throughout the oestrous cycle and after ovariectomy to determine whether GPR30 expression in central autonomic nuclei is correlated with circulating oestrogen levels. In the nucleus of the solitary tract (NTS), ventrolateral medulla (VLM) and periaqueductal gray (PAG) GPR30 mRNA, quantified by real-time PCR, was increased in proestrus and oestrus. In ovariectomised (OVX) rats, expression in NTS and VLM appeared increased compared to metoestrus, but in the hypothalamic paraventricular nucleus and PAG lower mRNA levels were seen in OVX. GPR30-like immunoreactivity (GPR30-LI) colocalised with Golgi in neurones in many brain areas associated with autonomic pathways, and analysis of numbers of immunoreactive neurones showed differences consistent with the PCR data. GPR30-LI was found in a variety of transmitter phenotypes, including cholinergic, serotonergic, catecholaminergic and nitrergic neurones in different neuronal groups. These observations support the view that GPR30 could act as a rapid transducer responding to oestrogen levels and thus modulate the activity of central autonomic pathways.

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Cardiac myofibroblasts (CMF) have a key role in the remodelling of the heart that occurs following a myocardial infarction. This remodelling can be initiated by increased myocardial levels of proinflammatory cytokines (eg, interleukin (IL)-1), that can stimulate cardiac myofibroblasts to express other proinflammatory cytokines and matrix metalloproteinases (MMPs). The p38 mitogen-activated protein kinase (MAPK) signalling pathway is also known to be detrimental in the myocardial remodelling process. There are four known p38 MAPK subtypes (α, β, γ and δ) and CMF express the α, γ and δ subtypes. The aim of this study was to determine the role of individual p38 subtypes in mediating IL-1-induced increases in proinflammatory cytokine and MMP expression in cultured cardiac myofibroblasts from different patients. Pharmacological inhibitors of p38-α/β (SB203580) and p38-α/β/γ/δ (BIRB-0796) inhibited IL-1-induced IL-6 and MMP-3 mRNA expression to similar extents, suggesting a key role for p38-α. Neither inhibitor affected IL-1-induced IL-1β or MMP-9 mRNA levels. Gene silencing with p38-α siRNA oligonucleotides selectively reduced p38-α protein expression by >95% and prevented consequent phosphorylation of the downstream substrate MAPKAPK2. However, p38-α silencing did not markedly inhibit phosphorylation of the MAPKAPK2 substrate HSP27. Furthermore, p38-α gene silencing did not reduce IL-1-induced expression of IL-6 or MMP-3 (or IL-1β or MMP-9). Thus, in contrast to results with pharmacological p38 MAPK inhibitors, gene silencing of p38-α in human cardiac myofibroblasts did not inhibit IL-1-induced IL-6 and MMP-3 expression. This raises interesting questions about pharmacological versus molecular strategies for inhibiting p38 MAPK subtypes in the remodelling heart.