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.
Background Leukocyte‐directed biosynthesis of specialized proresolving mediators (SPMs) orchestrates physiological inflammation after myocardial infarction. Deficiency of SPMs drives pathological and nonresolving inflammation, leading to heart failure (HF). Differences in SPMs and inflammatory responses caused by sex‐specific differences are of interest. We differentiated leukocyte‐directed biosynthesis of lipid mediators in male and female mice, focusing on leukocyte populations, structural remodeling, functional recovery, and survival rates. Methods and Results Risk‐free male and female C57BL/6 mice were selected as naïve controls or subjected to myocardial infarction surgery. Molecular and cellular mechanisms that differentiate survival, heart function, and structure and leukocyte‐directed lipid mediators were quantified to describe physiological inflammation after myocardial infarction. Female mice show improved survival in acute HF but no statistical difference during chronic HF compared with male mice. Female mice improved survival is marked with functional recovery and limited remodeling compared with male mice. Male and female mice are similarly responsive to arachidonate lipoxygenase ( LOX‐5 , LOX‐12 , LOX ‐15) or cyclooxygenase ( COX‐1 , COX‐2 ) in acute HF and particularly male infarcted heart had overall increased SPMs. Female cardiac healing is marked with the biosynthesis of differential p450‐derived product, particularly 11,12 epoxyeicosatrienoic acid in acute HF. A sex‐specific difference of dendritic cells in acute HF is distinct, with limited changes in chronic HF. Conclusions Cardiac repair is marked with increased SPM biosynthesis in male mice and amplified epoxyeicosatrienoic acid in female mice. Female mice showed improved survival, functional recovery, and limited remodeling, which are signs of fine‐tuned physiological inflammation after myocardial infarction. These results rationalize the sex‐specific precise therapies and differential treatments in acute and chronic HF.
Among the Carnivora, play behaviour is usually made up of motor patterns characteristic of predatory, agonistic and courtship behaviour. Domestic dogs are unusual in that play is routinely performed by adults, both socially, with conspecifics and with humans, and also asocially, with objects. This enhanced playfulness is commonly thought to be a side effect of paedomorphosis, the perpetuation of juvenile traits into adulthood, but here we suggest that the functions of the different types of play are sufficiently distinct that they are unlikely to have arisen through a single evolutionary mechanism. Solitary play with objects appears to be derived from predatory behaviour: preferred toys are those that can be dismembered, and a complex habituation-like feedback system inhibits play with objects that are resistant to alteration. Intraspecific social play is structurally different from interspecific play and may therefore be motivationally distinct and serve different goals; for example, dogs often compete over objects when playing with other dogs, but are usually more cooperative when the play partner is human. The majority of dogs do not seem to regard competitive games played with a human partner as "dominance" contests: rather, winning possession of objects during games appears to be simply rewarding. Play may be an important factor in sociality, since dogs are capable of extracting social information not only from games in which they participate, but also from games that they observe between third parties. We suggest that the domestic dog's characteristic playfulness in social contexts is an adaptive trait, selected during domestication to facilitate both training for specific purposes, and the formation of emotionally-based bonds between dog and owner. Play frequency and form may therefore be an indicator of the quality of dog-owner relationships.
Highlights 17 In contrast to equines, canine sport science has been poorly studied. 18 As the distance between consecutive upright hurdles increases, so do the take-off and 19 landing distances. 20 Take-off and landing distances further alter with the dog's skill level. 21 There are greater differences in jump kinematics when the distances between 22 consecutive hurdles are shorter. speeds differed for hurdle distances (P < 0.001) and level of skill (P < 0.001). There were 40 significant differences in apparent neck angle during take-off and landing (P < 0.001), lumbar 41 spine angles during take-off, bascule and landing (P < 0.01), and in shoulder angles during 42 the bascule phase (P < 0.05). The results indicate that agility dogs alter their jumping 43 patterns to accommodate the spacing between hurdles, which ultimately may impact long 44 term health and welfare due to altered kinematics.
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