Obesity superimposed on aging magnifies inflammation and delays the resolving response after myocardial infarction

Abstract

Polyunsaturated fatty acid (PUFA) intake has increased over the last 100 yr, contributing to the current obesogenic environment. Obesity and aging are prominent risk factors for myocardial infarction (MI). How obesity interacts with aging to alter the post-MI response, however, is unclear. We tested the hypothesis that obesity in aging mice would impair the resolution of post-MI inflammation. PUFA diet (PUFA aging group) feeding to 12-mo-old C57BL/6J mice for 5 mo showed higher fat mass compared with standard lab chow (LC)-fed young (LC young group; 3-5 mo old) or aging alone control mice (LC aging group). LC young, LC aging, and PUFA aging mice were subjected to coronary artery ligation to induce MI. Despite similar infarct areas post-MI, plasma proteomic profiling revealed higher VCAM-1 in the PUFA aging group compared with LC young and LC aging groups, leading to increased neutrophil infiltration in the PUFA aging group (P<0.05). Macrophage inflammatory protein-1γ and CD40 were also increased at day 1, and myeloperoxidase remained elevated at day 5, an observation consistent with delayed wound healing in the PUFA aging group. Lipidomic analysis showed higher levels of arachidonic acid and 12(S)-hydroxyeicosatetraenoic acid at day 1 post-MI in the PUFA aging group compared with the LC aging group (all P<0.05), thereby mediating neutrophil extravasation in the PUFA aging group. The inflammation-resolving enzymes 5-lipoxygenase, cyclooxygenase-2, and heme oxyegnase-1 were altered to delay wound healing post-MI in the PUFA aging group compared with LC young and LC aging groups. PUFA aging magnifies the post-MI inflammatory response and impairs the healing response by stimulating prolonged neutrophil trafficking and proinflammatory lipid mediators.

Obesity induced by high fat diet attenuates postinfarct myocardial remodeling and dysfunction in adult B6D2F1 mice

“…These results are further supported by the lack of effect of HFD on vasorelaxation response to acetylcholine or NO, or on arterial pressure, that remained stable throughout the study. Globally, our data are in agreement with recent studies [16,17,[33][34][35], that failed to document a role of diet-induced obesity in the development of heart remodeling and failure. Since hyperglycemia activates the cardiac intracellular renin-angiotensin system, which increases oxidative stress and cardiac fibrosis [36], the absence of hyperglycemia in our model could explain the preservation of function and heart morphology.…”

“…In a recent study, a short period of HFD feeding (from 24 h to 2 weeks) that did not induce obesity resulted in infarct size reduction and preserved function in an in vivo mouse model of transient coronary occlusion, while protection was lost when HFD feeding was extended to 6 weeks [38]. More recently, a comprehensive study by Lopez et al has analyzed the effect of moderated obesity on the myocardial response to a permanent coronary occlusion in aging mice [35]. This study showed that obesity induced with a n-6 polyunsaturated fatty acid-enriched diet increases LV dysfunction and mortality in aging mice at day 5 of ischemia by amplifying the acute proinflammatory response.…”

Myocardial infarction induces atrial inflammation that can be prevented by C1-esterase inhibitor

“…In addition, the patients with MI included in our study had a mean age of 60, which makes it representative of an ageing population. In mice, it was previously described that ageing and obesity combined results in an increased severity of post-MI inflammation 20. Therefore, this provides a further indication that epicardial adipose tissue may have played an important role in the cardiac inflammation observed in the patients with MI.…”

Cardiomyocyte-specific Bmal1 deletion in mice triggers diastolic dysfunction, extracellular matrix response, and impaired resolution of inflammation

“…To analyze myocyte area, wheat germ agglutinin (WGA) staining was performed. Formalinfixed, paraffin-embedded LV blocks were sectioned at 5-m thickness, deparaffinized, and rehydrated, as previously described (26). Alexa Fluor 488-conjugated WGA (Invitrogen) solution was added to the tissue in 1:1,000 dilution for 1 h. Samples were then washed with PBS and mounted with prolonged gold antifade reagent (Invitrogen).…”

“…The new homogenous solution was snapfrozen and used as fraction B insoluble protein. Total protein content was determined using the Bradford assay (26). A total of 10 g protein was loaded, electrophoresed on Criterion XT Bis-Tris 4 -12% 18-gel, MOPS buffer and transferred to a nitrocellulose membrane using material from Bio-Rad.…”