Abstract
Objective Myocardial ischemia and reperfusion (I/R) injury is associated with oxidative stress and inflammation, leading to scar development and malfunction. The marine omega-3 fatty acids (ω-3 FA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are mediating cardioprotection and improving clinical outcomes in patients with heart disease. Therefore, we tested the hypothesis that docosahexaenoic acid (DHA) supplementation prior to LAD occlusion-induced myocardial injury (MI) confers cardioprotection in mice. Methods C57BL/6N mice were placed on DHA or control diets (CD) beginning 7 d prior to 60 min LAD occlusion-induced MI or sham surgery. The expression of inflammatory mediators was measured via RT-qPCR. Besides FACS analysis for macrophage quantification and subtype evaluation, macrophage accumulation as well as collagen deposition was quantified in histological sections. Cardiac function was assessed using a pressure-volume catheter for up to 14 d. Results DHA supplementation significantly attenuated the induction of peroxisome proliferator-activated receptor-α (PPAR-α) (2.3 ± 0.4 CD vs. 1.4 ± 0.3 DHA) after LAD occlusion. Furthermore, TNF-α (4.0 ± 0.6 CD vs. 1.5 ± 0.2 DHA), IL-1β (60.7 ± 7.0 CD vs. 11.6 ± 1.9 DHA), and IL-10 (223.8 ± 62.1 CD vs. 135.5 ± 38.5 DHA) mRNA expression increase was diminished in DHA-supplemented mice after 72 h reperfusion. These changes were accompanied by a less prominent switch in α/β myosin heavy chain isoforms. Chemokine mRNA expression was stronger initiated (CCL2 6 h: 32.8 ± 11.5 CD vs. 78.8 ± 13.6 DHA) but terminated earlier (CCL2 72 h: 39.5 ± 7.8 CD vs. 8.2 ± 1.9 DHA; CCL3 72 h: 794.3 ± 270.9 CD vs. 258.2 ± 57.8 DHA) in DHA supplementation compared to CD mice after LAD occlusion. Correspondingly, DHA supplementation was associated with a stronger increase of predominantly alternatively activated Ly6C-positive macrophage phenotype, being associated with less collagen deposition and better LV function (EF 14 d: 17.6 ± 2.6 CD vs. 31.4 ± 1.5 DHA). Conclusion Our data indicate that DHA supplementation mediates cardioprotection from MI via modulation of the inflammatory response with timely and attenuated remodeling. DHA seems to attenuate MI-induced cardiomyocyte injury partly by transient PPAR-α downregulation, diminishing the need for antioxidant mechanisms including mitochondrial function, or α- to β-MHC isoform switch.
Highlights
Coronary heart disease (CHD) is a significant health concern in the western world with increasing prevalence and the leading cause of death in Europe, accounting for €60 billion in health care costs annually [1]
To evaluate whether docosahexaenoic acid (DHA) pretreatment attenuates the development of myocardial injury (MI)-induced LV dysfunction, we examined the pressure-volume parameters of LV function in control diets (CD)- and DHA-pretreated mice 14 days after 60 min of LAD occlusion-induced myocardial infarction (MI)
left ventricular end-diastolic pressure (LVEDP) remained at sham levels in DHA-supplemented mice and was significantly lower compared to CD mice 14 days after MI (Figure 1(b))
Summary
Coronary heart disease (CHD) is a significant health concern in the western world with increasing prevalence and the leading cause of death in Europe, accounting for €60 billion in health care costs annually [1]. An early intervention reestablishing coronary perfusion is essential for myocardial salvage after MI, reperfusion itself triggers a further injury [3] This so-called ischemia/reperfusion (I/R) injury is an inherent response to the restoration of blood flow involving numerous mechanisms including the increased generation of reactive oxygen species (ROS), acute calcium overload of cardiomyocytes, and opening of the mitochondrial permeability transition pore (MPTP), leading to uncoupled oxidative phosphorylation and contractile dysfunction. These insults further aggravate myocardial remodeling after MI, through increased generation of proinflammatory and proapoptotic molecules resulting in myocyte death, collagen deposition, and scar formation, exacerbating the development of heart failure [4, 5]. Attenuating I/R injury is an important target for cardioprotection and a promising therapeutic approach to improve clinical outcomes after an acute MI
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