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BACKGROUND: Atrial fibrillation (AF) is promoted by various stimuli like angiotensin II, endothelin-1, epinephrine/norepinephrine, vagal activation, or mechanical stress, all of which activate receptors coupled to G-proteins of the Ga(q)/Ga(11)-family (G(q)). Besides pro-fibrotic and pro-inflammatory effects, G(q)-mediated signaling induces inositol trisphosphate receptor (IP(3)R)-mediated intracellular Ca(2+) mobilization related to delayed after-depolarisations and AF. However, direct evidence of arrhythmogenic G(q)-mediated signaling is absent. METHODS AND RESULTS: To define the role of G(q) in AF, transgenic mice with tamoxifen-inducible, cardiomyocyte-specific Ga(q)/Ga(11)-deficiency (G(q)-KO) were created and exposed to intracardiac electrophysiological studies. Baseline electrophysiological properties, including heart rate, sinus node recovery time, and atrial as well as AV nodal effective refractory periods, were comparable in G(q)-KO and control mice. However, inducibility and mean duration of AF episodes were significantly reduced in G(q)-KO mice-both before and after vagal stimulation. To explore underlying mechanisms, left atrial cardiomyocytes were isolated from G(q)-KO and control mice and electrically stimulated to study Ca(2+)-mobilization during excitation-contraction coupling using confocal microscopy. Spontaneous arrhythmogenic Ca(2+) waves and sarcoplasmic reticulum content-corrected Ca(2+) sparks were less frequent in G(q)-KO mice. Interestingly, nuclear but not cytosolic Ca(2+) transient amplitudes were significantly decreased in G(q)-KO mice. CONCLUSION: G(q)-signaling promotes arrhythmogenic atrial Ca(2+)-release and AF in mice. Targeting this pathway, ideally using G(q)-selective, biased receptor ligands, may be a promising approach for the treatment and prevention of AF. Importantly, the atrial-specific expression of the G(q)-effector IP(3)R confers atrial selectivity mitigating the risk of life-threatening ventricular pro-arrhythmic effects.

The pathogenesis of hypertension is known to involve a diverse range of contributing factors including genetic, environmental, hormonal, hemodynamic and inflammatory forces, to name a few. There is mounting evidence to suggest that the gut microbiome plays an important role in the development and pathogenesis of hypertension. The gastrointestinal tract, which houses the largest compartment of immune cells in the body, represents the intersection of the environment and the host. Accordingly, lifestyle factors shape and are modulated by the microbiome, modifying the risk for hypertensive disease. One well-studied example is the consumption of dietary fibers, which leads to the production of short-chain fatty acids and can contribute to the expansion of anti-inflammatory immune cells, consequently protecting against the progression of hypertension. Dietary interventions such as fasting have also been shown to impact hypertension via the microbiome. Studying the microbiome in hypertensive disease presents a variety of unique challenges to the use of traditional model systems. Integrating microbiome considerations into preclinical research is crucial, and novel strategies to account for reciprocal host-microbiome interactions, such as the wildling mouse model, may provide new opportunities for translation. The intricacies of the role of the microbiome in hypertensive disease is a matter of ongoing research, and there are several technical considerations which should be accounted for moving forward. In this review we provide insights into the host-microbiome interaction and summarize the evidence of its importance in the regulation of blood pressure. Additionally, we provide recommendations for ongoing and future research, such that important insights from the microbiome field at large can be readily integrated in the context of hypertension.

Recent literature indicates a potential importance of the gut microbiota for immune mediated diseases. For instance, decreased diversity of commensals or an outgrowth of some bacterial strains, referred to as gut dysbiosis, was recently linked to hypertension, colitis, lupus, rheumatoid arthritis and multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE) as pivotal animal model of MS revealed a potential importance of microbial metabolites, including short-chain fatty acids or tryptophan metabolites. Both metabolites may influence the disease by modulation of the immune system, mainly by inducing regulatory T cells. These studies prompted researchers to investigate the contribution of the gut microbiota and microbial metabolites in the pathogenesis of MS. This review summarizes recent findings on the gut microbiota in MS patients and discusses the potential mechanisms how microbial metabolites may affect neuroinflammation. Many of these studies have been performed in the EAE model and were later reversely translated to humans. We also give a short summary on dietary high-salt effects on microbiota components and discuss the potential relevance of high-salt as a risk factor in MS. This article is protected by copyright. All rights reserved.

Management of protein homeostasis by the ubiquitin-proteasome system is critical for atherosclerosis development. Recent studies showed controversial results on the role of immunoproteasome (IP) subunit {beta}5i/LMP7 in maintenance of protein homeostasis under cytokine induced oxidative stress. The present study aimed to investigate the effect of {beta}5i/LMP7-deficiency on the initiation and progression of atherosclerosis as a chronic inflammatory, immune cell driven disease. LDLR(-/-)LMP7(-/-) and LDLR(-/-) mice were fed a Western-type diet for either 6 or 24 weeks to induce early and advanced stage atherosclerosis, respectively. Lesion burden was similar between genotypes in both stages. Macrophage content and abundance of polyubiquitin conjugates in aortic root plaques were unaltered by {beta}5i/LMP7-deficiency. In vitro experiments using bone marrow-derived macrophages (BMDM) showed that {beta}5i/LMP7-deficiency did not influence macrophage polarization or accumulation of polyubiquitinated proteins and cell survival upon hydrogen peroxide and interferon-γ treatment. Analyses of proteasome core particle composition by Western blot revealed incorporation of standard proteasome subunits in {beta}5i/LMP7-deficient BMDM and spleen. Chymotrypsin-, trypsin- and caspase-like activities assessed by using short fluorogenic peptides in BMDM whole cell lysates were similar in both genotypes. Taken together, deficiency of IP subunit {beta}5i/LMP7 does not disturb protein homeostasis and does not aggravate atherogenesis in LDLR(-/-) mice.