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The recent discovery that anti-angiogenic, pro-apoptotic and pro-inflammatory N-terminal 16-kDa prolactin subform (16-kDa Prl) is generated under enhanced oxidative stress and yielding adverse cardiac effects, prompted us to investigate the potential role of prolactin and its cleaved 16-kDa form in myocardial ischemia/reperfusion (I/R) injury.
In the current study we demonstrate that enhanced levels of serum prolactin (Prl) and cathepsin D (CD) activity in patients with acute myocardial infarction (AMI) were associated with the generation of N-terminal 16-kDa subform.
In a murine model of myocardial I/R with previous LAD (left anterior descending artery) ligation for 50 minutes, blockage of endogenous Prl release by the dopamine D2 receptor agonist bromocriptine limited infarct size 24 hours post-reperfusion and preserved left ventricular (LV) function after 14 days of reperfusion.
Additionally, we demonstrate that after blockage of endogenous Prl release, the subsequent application of a recombinant mutant, prolactin isoform, which is not cleaved into the 16-kDa subform, significantly limited the extent of cardiac injury compared to the well-cleaved corresponding wildtype prolactin isoform 24 hours post-reperfusion.
I/R injury-induced up-regulation of pro-inflammatory mediators (e.g. TNF-α, CCL-2, CXCL2) and extravasation of inflammatory infiltrates were significantly reduced in bromocriptine treated mice than untreated controls.
The bromocriptine induced cardiac protection was mainly addicted to inhibition of 16-kDa Prl formation, as myocardium treated with the mutant prolactin isoform displayed substantially less inflammatory cell infiltration and cytokine expression than myocardium treated with the wildtype prolactin isoform.
In addition, we discovered that recombinant 16-kDa Prl markedly induced the expression of proinflammatory cytokines via activation of NF-κB signalling in neonatal rat cardiomyocytes.