Lipoxygenase Signaling in Heart Failure Pathology

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Summary: Chronic inflammation following myocardial infarction (MI) can progress to heart failure (HF) with excess morbidity and mortality; therefore, improvement in left ventricular (LV) function and survival after MI are hard endpoints that provide the ultimate test of therapeutic efficacy. While multiple factors impact adverse cardiac remodeling and HF progression, emerging studies lend credence to the concept that aberrant lipid metabolism contributes importantly to chronic inflammation and subsequent HF. Traditionally, all lipoxygenase (LOX)-derived lipid mediators have been considered proinflammatory and detrimental. However, acute inflammation is necessary for early healing; therefore, rather than inhibition of all inflammation, the goal of therapy should be to achieve an optimal balance between inflammation-promoting and -resolving factors. Our data indicate that deletion of 12/15LOX in mice delays HF post-MI, improves infarct healing, and reduces LV dysfunction and mortality by promoting the formation of the resolving lipid mediators, cypoxins that polarize leukocytes to a reparative phenotype. These data suggest that 12/15LOX activity underlies non-resolving inflammation following MI, thereby negatively impacting LV function and mortality. Our data in mice and patients with HF suggest that an eicosanoid product of 12/15LOX-induced arachidonic acid metabolism, 12(S)- hydroxyeicosatetraenoic acid, delays leukocyte clearance in the post-MI heart, delaying inflammation resolution. Which specific myeloid-leukocyte population contributes to bioactive lipid mediator generation after MI remains unclear; our data point to a critical role for macrophages. Thus, we hypothesize that macrophage- produced 12/15LOX is a key regulator of both inflammation-triggering and -resolving pathway(s) after MI healing, and these must be balanced to alleviate the progression to HF. To test this hypothesis, we propose three aims. Aim 1: Determine if 12/15LOX deficiency reduces inflammatory mediators to control overactive inflammation in acute HF after MI (days 1 to 5), using a myeloid-specific 12/15LOX-knockout mice. Aim 2: Test whether myeloid-specific 12/15LOX deficiency limits proinflammatory and promotes proresolving mediators biosynthesis to promote effective healing after MI, and thereby delays the progression to chronic HF. We will determine the proinflammatory and proresolving mediators in the infarcted area using quantitative and imaging mass spectrometry approaches that were technologically unfeasible before, and determine the mechanism by which macrophage-specific 12/15LOX balances proinflammatory and proresolving mediators. Aim 3: Establish whether post-MI inhibition of 12/15LOX augments the biosynthesis of proresolving lipids acutely and chronically after MI, and thereby facilitates LV healing and repair. Collectively, the proposed studies will define the role of 12/15LOX in the initiation, resolution, and progression of inflammation post-MI. To accomplish this, we have enlisted inflammation, HF, and biostatistics experts to complement our expertise in lipid signaling. The new knowledge gained will advance the development of novel therapeutic targets/drugs to ameliorate HF.