Epigenetic regulation of histone H3K27 methylation has recently emerged as a key step during alternative immunoregulatory M2-like macrophage polarization; known to impact cardiac repair after ...Myocardial Infarction (MI). We hypothesized that EZH2, responsible for H3K27 methylation, could act as an epigenetic checkpoint regulator during this process. We demonstrate for the first time an ectopic EZH2, and putative, cytoplasmic inactive localization of the epigenetic enzyme, during monocyte differentiation into M2 macrophages in vitro as well as in immunomodulatory cardiac macrophages in vivo in the post-MI acute inflammatory phase. Moreover, we show that pharmacological EZH2 inhibition, with GSK-343, resolves H3K27 methylation of bivalent gene promoters, thus enhancing their expression to promote human monocyte repair functions. In line with this protective effect, GSK-343 treatment accelerated cardiac inflammatory resolution preventing infarct expansion and subsequent cardiac dysfunction in female mice post-MI in vivo. In conclusion, our study reveals that pharmacological epigenetic modulation of cardiac-infiltrating immune cells may hold promise to limit adverse cardiac remodeling after MI.
Perceptual decision-making tasks are essential to many fields of neuroscience. Current protocols generally reward deprived animals with water. However, balancing animals’ deprivation level with their ...well-being is challenging, and trial number is limited by satiation. Here, we present electrical stimulation of the medial forebrain bundle (MFB) as an alternative that avoids deprivation while yielding stable motivation for thousands of trials. Using licking or lever press as a report, MFB animals learnt auditory discrimination tasks at similar speed to water-deprived mice. Moreover, they more reliably reached higher accuracy in harder tasks, performing up to 4,500 trials per session without loss of motivation. MFB stimulation did not impact the underlying sensory behavior since psychometric parameters and response times are preserved. MFB mice lacked signs of metabolic or behavioral stress compared with water-deprived mice. Overall, MFB stimulation is a highly promising tool for task learning because it enhances task performance while avoiding deprivation.
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•Medial forebrain bundle (MFB) stimulation can be used as a reward in mouse behavior studies•Training with MFB stimulation improves performance on perceptual discrimination tasks•MFB-stimulated mice perform thousands of trials per session without motivation loss•MFB stimulation reduces signs of stress compared with deprivation protocols
Training animals on decision-making tasks to measure their perceptual abilities and match this to ongoing neural activity is an essential part of integrative neuroscience. This can be achieved by depriving animals to motivate them to respond for a reward such as water or food. This limits sessions to a few hundred trials per day before animals reach satiation and requires carefully balancing deprivation with animal well-being. Therefore, we developed intracranial stimulation of the MFB as a reward because this does not lead to satiation and avoids deprivation.
Verdier et al. show that MFB stimulation can be used as a reward to train mice on perceptual discrimination tasks without deprivation. With this approach, mice displayed better performance, which they maintained for up to 4,500 trials per session.
Objective: Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent hereditary kidney disease and is generally due to mutations in PKD1 and PKD2, encoding polycystins 1 and 2. In ...ADPKD, hypertension and cardiovascular (CV) disorders are highly prevalent but their mechanisms are partially understood. The objective of this study was to determine whether hypertension and the CV disorders of ADPKD are a consequence of the endothelial deficiency in the polycystin complex, rather than to the kidney disease, as is currently believed. Design and method: Since endothelial cells express the polycystin complex, where it plays a central role in the mechanotransduction of blood flow, we generated a murine model with inducible deletion of Pkd1 in endothelial cells (Cdh5-CreERT2;Pkd1fl/fl) to specifically determine the role of endothelial polycystin-1 in ADPKD. We nalysed the endothelial phenotype associated with Pkd1 deficiency, invasive and non-invasive blood pressure, vascular function on isolated vessels, and echocardiography. The impact on the development of a model of aorto-cava arterio-venous fistula and on the CV consequences of superimposed chronic kidney disease were nalysed to further establish the clinical relevance of our results. Results: As expected, transgenic mice presented normal kidney structure and function. Endothelial deletion of Pkd1 induced endothelial dysfunction, as demonstrated by impaired flow-mediated dilatation of resistance arteries and impaired relaxation to acetylcholine, increased blood pressure and prevented the normal development of arterio-venous fistula. In experimental chronic kidney disease induced by subtotal nephrectomy, endothelial deletion of Pkd1 further aggravated endothelial dysfunction, vascular remodelling and heart hypertrophy. Conclusions: Altogether, this study provides the first in vivo demonstration that specific deletion of Pkd1 in endothelial cells promotes endothelial dysfunction and hypertension independently of kidney cysts and of impaired kidney function, impairs arterio-venous fistula development and potentiates the cardiovascular alterations associated with chronic kidney disease. It establishes the endothelium as a significant contributor to cardiovascular disease in ADPKD.
Inhibitors of soluble epoxide hydrolase (sEH), which catalyzes the hydrolysis of various natural epoxides to their corresponding diols, present an opportunity for developing oral drugs for a range of ...human cardiovascular and inflammatory diseases, including, among others, diabetes and neuropathic pain. However, some evidence suggests that their administration may precipitate the development of pulmonary hypertension (PH). We thus evaluated the impact of chronic oral administration of the sEH inhibitor TPPU (N-1-(1-Oxopropyl)-4-piperidinyl-N'-4-(trifluoromethoxy)phenyl-urea) on hemodynamics, pulmonary vascular reactivity, and remodeling, as well as on right ventricular (RV) dimension and function at baseline and in the Sugen (SU5416) + hypoxia (SuHx) rat model of severe PH. Treatment with TPPU started 5 weeks after SU5416 injection for 3 weeks. No differences regarding the increase in pulmonary vascular resistance, remodeling, and inflammation, nor the abolishment of phenylephrine-induced pulmonary artery constriction, were noted in SuHx rats. In addition, TPPU did not modify the development of RV dysfunction, hypertrophy, and fibrosis in SuHx rats. Similarly, none of these parameters were affected by TPPU in normoxic rats. Complementary in vitro data demonstrated that TPPU reduced the proliferation of cultured human pulmonary artery-smooth muscle cells (PA-SMCs). This study demonstrates that inhibition of sEH does not induce nor aggravate the development of PH and RV dysfunction in SuHx rats. In contrast, a potential beneficial effect against pulmonary artery remodeling in humans is suggested.
Cardiovascular diseases (CVD) are the leading cause of premature death and disability in humans that are closely related to lipid metabolism and signaling. This study aimed to assess whether ...circulating lysophospholipids (LPL), lysophosphatidic acids (LPA) and monoacylglycerols (MAG) may be considered as potential therapeutic targets in CVD. For this objective, plasma levels of 22 compounds (13 LPL, 6 LPA and 3 MAG) were monitored by liquid chromatography coupled with tandem mass spectrometry (HPLC/MS2) in different rat models of CVD, i.e., angiotensin-II-induced hypertension (HTN), ischemic chronic heart failure (CHF) and sugen/hypoxia(SuHx)-induced pulmonary hypertension (PH). On one hand, there were modest changes on the monitored compounds in HTN (LPA 16:0, 18:1 and 20:4, LPC 16:1) and CHF (LPA 16:0, LPC 18:1 and LPE 16:0 and 18:0) models compared to control rats but these changes were no longer significant after multiple testing corrections. On the other hand, PH was associated with important changes in plasma LPA with a significant increase in LPA 16:0, 18:1, 18:2, 20:4 and 22:6 species. A deleterious impact of LPA was confirmed on cultured human pulmonary smooth muscle cells (PA-SMCs) with an increase in their proliferation. Finally, plasma level of LPA(16:0) was positively associated with the increase in pulmonary artery systolic pressure in patients with cardiac dysfunction. This study demonstrates that circulating LPA may contribute to the pathophysiology of PH. Additional experiments are needed to assess whether the modulation of LPA signaling in PH may be of interest.
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•The physiological role of the phosphatase activity of the bifunctional sEH is unknown.•CRISPR/Cas9-mediated inhibition of sEH phosphatase in rats induces a lean ...phenotype.•Potentiation of brown adipose tissue thermogenesis drives increased energy expenditure in sEH phosphatase knock-in rats.•sEH phosphatase knock-in rats have an increased cardiac contractility and were protected against cardiac ischemia–reperfusion injury.•The phosphatase activity of sEH represents a new potential target to fight against obesity and cardiac ischemic complications.
Although the physiological role of the C-terminal hydrolase domain of the soluble epoxide hydrolase (sEH-H) is well investigated, the function of its N-terminal phosphatase activity (sEH-P) remains unknown.
This study aimed to assess in vivo the physiological role of sEH-P.
CRISPR/Cas9 was used to generate a novel knock-in (KI) rat line lacking the sEH-P activity.
The sEH-P KI rats has a decreased metabolism of lysophosphatidic acids to monoacyglycerols. KI rats grew almost normally but with less weight and fat mass gain while insulin sensitivity was increased compared to wild-type rats. This lean phenotype was more marked in males than in female KI rats and mainly due to decreased food consumption and enhanced energy expenditure. In fact, sEH-P KI rats had an increased lipolysis allowing to supply fatty acids as fuel to potentiate brown adipose thermogenesis under resting condition and upon cold exposure. The potentiation of thermogenesis was abolished when blocking PPARγ, a nuclear receptor activated by intracellular lysophosphatidic acids, but also when inhibiting simultaneously sEH-H, showing a functional interaction between the two domains. Furthermore, sEH-P KI rats fed a high-fat diet did not gain as much weight as the wild-type rats, did not have increased fat mass and did not develop insulin resistance or hepatic steatosis. In addition, sEH-P KI rats exhibited enhanced basal cardiac mitochondrial activity associated with an enhanced left ventricular contractility and were protected against cardiac ischemia–reperfusion injury.
Our study reveals that sEH-P is a key player in energy and fat metabolism and contributes together with sEH-H to the regulation of cardiometabolic homeostasis. The development of pharmacological inhibitors of sEH-P appears of crucial importance to evaluate the interest of this promising therapeutic strategy in the management of obesity and cardiac ischemic complications.
Background: Autosomal dominant polycystic kidney disease is the most frequent hereditary kidney disease and is generally due to mutations in PKD1 and PKD2 , encoding polycystins 1 and 2. In autosomal ...dominant polycystic kidney disease, hypertension and cardiovascular disorders are highly prevalent, but their mechanisms are partially understood. Methods: Since endothelial cells express the polycystin complex, where it plays a central role in the mechanotransduction of blood flow, we generated a murine model with inducible deletion of Pkd1 in endothelial cells ( Cdh5-Cre ERT2 ; Pkd1 fl/fl ) to specifically determine the role of endothelial polycystin-1 in autosomal dominant polycystic kidney disease. Results: Endothelial deletion of Pkd1 induced endothelial dysfunction, as demonstrated by impaired flow-mediated dilatation of resistance arteries and impaired relaxation to acetylcholine, increased blood pressure and prevented the normal development of arteriovenous fistula. In experimental chronic kidney disease induced by subtotal nephrectomy, endothelial deletion of Pkd1 further aggravated endothelial dysfunction, vascular remodeling, and heart hypertrophy. Conclusions: Altogether, this study provides the first in vivo demonstration that specific deletion of Pkd1 in endothelial cells promotes endothelial dysfunction and hypertension, impairs arteriovenous fistula development, and potentiates the cardiovascular alterations associated with chronic kidney disease.
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