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.
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Funding Funded by a British Heart Foundation project grant.
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