Lack of resolution sensor drives age-related cardiometabolic and cardiorenal defects and impedes inflammation-resolution in heart failure

Abstract

ObjectiveRecently, we observed that the specialized proresolving mediator (SPM) entity resolvin D1 activates lipoxin A4/formyl peptide receptor 2 (ALX/FPR2), which facilitates cardiac healing and persistent inflammation is a hallmark of impaired cardiac repair in aging. Splenic leukocyte-directed SPMs are essential for the safe clearance of inflammation and cardiac repair after injury; however, the target of SPMs remains undefined in cardiac healing and repair.MethodsTo define the mechanistic basis of ALX/FPR2 as a resolvin D1 target, ALX/FPR2-null mice were examined extensively. The systolic-diastolic heart function was assessed using echocardiography, leukocytes were phenotyped using flow cytometry, and SPMs were quantitated using mass spectrometry. The presence of cardiorenal syndrome was validated using histology and renal markers.ResultsLack of ALX/FPR2 led to the development of spontaneous obesity and diastolic dysfunction with reduced survival with aging. After cardiac injury, ALX/FPR2−/− mice showed lower expression of lipoxygenases (−5, −12, −15) and a reduction in SPMs in the infarcted left ventricle and spleen, indicating nonresolving inflammation. Reduced SPM levels in the infarcted heart and spleen are suggestive of impaired cross-talk between the injured heart and splenic leukocytes, which are required for the resolution of inflammation. In contrast, cyclooxygenases (−1 and −2) were over amplified in the infarcted heart. Together, these results suggest interorgan signaling in which the spleen acts as both an SPM biosynthesizer and supplier in acute heart failure. ALX/FPR2 dysfunction magnified obesogenic cardiomyopathy and renal inflammation (↑NGAL, ↑TNF-α, ↑CCL2, ↑IL-1β) with elevated plasma creatinine levels in aging mice. At the cellular level, ALX/FPR2−/− mice showed impairment of macrophage phagocytic function ex-vivo with expansion of neutrophils after myocardial infarction.ConclusionsLack of ALX/FPR2 induced obesity, reduced the life span, amplified leukocyte dysfunction, and facilitated profound interorgan nonresolving inflammation. Our study shows the integrative and indispensable role of ALX/FPR2 in lipid metabolism, cardiac inflammation–resolution processes, obesogenic aging, and renal homeostasis.

Deficit of resolution receptor magnifies inflammatory leukocyte directed cardiorenal and endothelial dysfunction with signs of cardiomyopathy of obesity

“…Every aspect of the immune response including presentation of CCR2, complex MHCII, immune cell differentiation, and leukocytes class switching activity in wound healing intimately links with cell metabolism and resolution of inflammation 40‐42 . Previous reports suggest that endogenous/exogenous/agonist‐based action of the ALX receptor facilitates the resolution of inflammation, anti‐inflammatory action, and cardiac repair, in contrast, the dysfunction of ALX receptor leads to non‐resolving inflammation with lower survival 18,21,43‐46 . Here, we present that obesity‐prone ALX −/− mice drives; (a) dysregulation of energy metabolism thereby developing an obesogenic phenotype leading to structural remodeling, perturbed electrical changes, and weakened myocardium strain of the heart; (b) activation of splenic CCR2 + macrophages that over prime CCL cluster of chemokines with the initiation of arrhythmogenic gene expression in the left ventricle; and (c) age‐related cardiorenal and endothelial dysfunction.…”

“…The age of 4 months old is considered middleaged mice based on our previous life span measurement in ALX −/− mice. 18 Two sets of age groups were compared with WT age-matched controls for molecular, cellular, and histological experiments. To comply with a systems biology approach, tissue organs such as spleen, heart, and kidney from all four groups were used to define the role of ALX receptor in obesity and aging-induced suboptimal inflammation in the progression of cardiovascular disease ( Figure 1A; study design).…”

Race‐based and sex‐based differences in bioactive lipid mediators after myocardial infarction

“…In the present report, we quantify the essential fatty acids and define the possible immune responsive SPM signatures in patients undergoing PCI after an acute STEMI event. We also examined the bioactive lipid mediators because these serve as molecular messengers derived from AA, DHA, and EPA and act as necessary initiators of early inflammation and resolution pathways . We have three key findings: (i) heterogeneous activation of fatty acids; (ii) profound expansion of monohydroxyl fatty acids such as 12‐HETE, 14‐HDHA, and 17‐HDHA; and (iii) distinct increase of SPM signature in Black and White patients, particularly higher RvE1 in White male patients compared with Black male patients.…”

Regulation of Inflammation and Oxidative Stress by Formyl Peptide Receptors in Cardiovascular Disease Progression

“…At the cellular level, FPR2 −/− mice have impairment of macrophage phagocytic function ex-vivo with an expansion of neutrophils after myocardial infarction. This suggests that blockade of FPR2 functions impairs biosynthesis of specialized proresolving mediators amplifying unresolved inflammation after cardiac injury [ 140 ].…”