Neutrophils in Post-myocardial Infarction Inflammation: Damage vs. Resolution?

Inflammation not only plays a crucial role in acute ischemic cardiac injury, but also contributes to post-infarction repair and remodeling. Traditionally, neutrophils have been merely considered as detrimental in the setting of an acute myocardial infarction. However, recently published studies demonstrated that neutrophils might also play an important role in cardiac repair by regulating reparative processes. An emerging concept is that different neutrophil subsets exist, which might exhibit separate functional properties. In support of the existence of distinct neutrophil subsets in the ischemic heart, transcriptional changes in cardiac neutrophils have been reported within the first few days after myocardial infarction. In addition, there is an increasing awareness of sex-specific differences in many physiological and pathophysiological responses, including cardiovascular parameters and inflammation. Of particular interest in this context are recent experimental data dissecting sex-specific differences in neutrophil signaling after myocardial infarction. Unraveling the distinct and possibly stage-dependent properties of neutrophils in cardiac repair may provide new therapeutic strategies in order to improve the clinical outcome for myocardial infarction patients. This review will briefly discuss recent advances in our understanding of the neutrophil functional repertoire and emerging insights of sex-specific differences in post-myocardial infarction inflammatory responses

Neutrophils in Post-myocardial Infarction Inflammation: Damage vs. Resolution?

Inflammation not only plays a crucial role in acute ischemic cardiac injury, but also contributes to post-infarction repair and remodeling. Traditionally, neutrophils have been merely considered as detrimental in the setting of an acute myocardial infarction. However, recently published studies demonstrated that neutrophils might also play an important role in cardiac repair by regulating reparative processes. An emerging concept is that different neutrophil subsets exist, which might exhibit separate functional properties. In support of the existence of distinct neutrophil subsets in the ischemic heart, transcriptional changes in cardiac neutrophils have been reported within the first few days after myocardial infarction. In addition, there is an increasing awareness of sex-specific differences in many physiological and pathophysiological responses, including cardiovascular parameters and inflammation. Of particular interest in this context are recent experimental data dissecting sex-specific differences in neutrophil signaling after myocardial infarction. Unraveling the distinct and possibly stage-dependent properties of neutrophils in cardiac repair may provide new therapeutic strategies in order to improve the clinical outcome for myocardial infarction patients. This review will briefly discuss recent advances in our understanding of the neutrophil functional repertoire and emerging insights of sex-specific differences in post-myocardial infarction inflammatory responses

Haematopoietic and cardiac GPR55 synchronize post-myocardial infarction remodelling

While classical cannabinoid receptors are known to crucially impact on myocardial infarction (MI) repair, a function of the cannabinoid-sensitive receptor GPR55 herein is poorly understood. We investigated the role of GPR55 in cardiac physiology and post-MI inflammation and remodelling. Global GPR55-/- and wildtype (WT) mice were basally characterized or assigned to 1, 3 or 28~days permanent MI and subsequently analysed via pro-inflammatory and pro-hypertrophic parameters. GPR55-/- deficiency was basally associated with bradycardia, increased diastolic LV volume and sarcomere length and a subtle inflammatory phenotype. While infarct size and myeloid cell infiltration were unaffected by GPR55 depletion, acute cardiac chemokine production was prolonged post-MI. Concurrently, GPR55-/- hearts exhibited a premature expansion of pro-reparative and phagocytic macrophages paralleled by early up-regulation of extracellular matrix (ECM) factors 3~days post-MI, which could be mimicked by sole haematopoietic GPR55 depletion. Moreover, global GPR55 deficiency mitigated MI-induced foetal gene re-programming and cardiomyocyte hypertrophy, culminating in aggravated LV dilatation and infarct expansion. GPR55 regulates cardiac homeostasis and ischaemia responses by maintaining adequate LV filling and modulating three crucial processes post-MI: wound healing kinetics, cardiomyocyte hypertrophy and maladaptive remodelling

Assessing structural and functional responses of murine hearts to acute and sustained β-adrenergic stimulation in vivo

AbstractIntroductionGiven the importance of β-adrenoceptor signalling in regulating cardiac structure and function, robust protocols are required to assess potential alterations in such regulation in murine models in vivo.MethodsEchocardiography was performed in naïve and stressed (isoprenaline; 30μg/g/day s.c. for up to 14days) mice, in the absence or presence of acute β-adrenergic stimulation (dobutamine 0.75μg/g, i.p.). Controls received saline infusion and/or injection. Hearts were additionally analysed gravimetrically, histologically and biochemically.ResultsIn naïve mice, acute β-adrenoceptor stimulation with dobutamine increased heart rate, left ventricular (LV) fractional shortening (LVFS), ejection fraction (LVEF) and wall thickness and decreased LV diameter (p<0.05). In stressed mice, dobutamine failed to induce further inotropic and chronotropic responses. Furthermore, following dobutamine injection, these mice exhibited lower LVEF and LVFS at identical heart rates, relative to corresponding controls. Sustained isoprenaline infusion induced LV hypertrophy (increased heart weight, heart weight/body weight ratio, heart weight/tibia length ratio and LV wall thickness (p<0.05)) by 3days, with little further change at 14days. In contrast, increases in LVEF and LVFS were seen only at 14days (p<0.05).DiscussionWe describe protocols for and illustrative data from the assessment of murine cardiac responses to acute and sustained β-adrenergic stimulation in vivo, which would be of value in determining the impact of genetic or pharmacological interventions on such responses. Additionally, our data indicate that acute dobutamine stimulation unmasks early signs of LV dysfunction in the remodelled heart, even at a stage when basal function is enhanced

Author Correction:Non-Invasive whole-body detection of complement activation using radionuclide imaging in a mouse model of myocardial ischaemia-reperfusion injury

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Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure

SummaryMitochondrial reactive oxygen species (ROS) play a central role in most aging-related diseases. ROS are produced at the respiratory chain that demands NADH for electron transport and are eliminated by enzymes that require NADPH. The nicotinamide nucleotide transhydrogenase (Nnt) is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Here, we show that pathological metabolic demand reverses the direction of the Nnt, consuming NADPH to support NADH and ATP production, but at the cost of NADPH-linked antioxidative capacity. In heart, reverse-mode Nnt is the dominant source for ROS during pressure overload. Due to a mutation of the Nnt gene, the inbred mouse strain C57BL/6J is protected from oxidative stress, heart failure, and death, making its use in cardiovascular research problematic. Targeting Nnt-mediated ROS with the tetrapeptide SS-31 rescued mortality in pressure overload-induced heart failure and could therefore have therapeutic potential in patients with this syndrome