4-Methylumbelliferone improves the thermogenic capacity of brown adipose tissue.

Therapeutic increase of brown adipose tissue (BAT) thermogenesis is of great interest as BAT activation counteracts obesity and insulin resistance. Hyaluronan (HA) is a glycosaminoglycan, found in the extracellular matrix, which is synthesized by HA synthases (Has1/Has2/Has3) from sugar precursors and accumulates in diabetic conditions. Its synthesis can be inhibited by the small molecule 4-methylumbelliferone (4-MU). Here, we show that the inhibition of HA-synthesis by 4-MU or genetic deletion of Has2/Has3 improves BAT`s thermogenic capacity, reduces body weight gain, and improves glucose homeostasis independently from adrenergic stimulation in mice on diabetogenic diet, as shown by a magnetic resonance T2 mapping approach. Inhibition of HA synthesis increases glycolysis, BAT respiration and uncoupling protein 1 expression. In addition, we show that 4-MU increases BAT capacity without inducing chronic stimulation and propose that 4-MU, a clinically approved prescription-free drug, could be repurposed to treat obesity and diabetes

Trained Innate Immunity in Animal Models of Cardiovascular Diseases

Acquisition of immunological memory is an important evolutionary strategy that evolved to protect the host from repetitive challenges from infectious agents. It was believed for a long time that memory formation exclusively occurs in the adaptive part of the immune system with the formation of highly specific memory T cells and B cells. In the past 10–15 years, it has become clear that innate immune cells, such as monocytes, natural killer cells, or neutrophil granulocytes, also have the ability to generate some kind of memory. After the exposure of innate immune cells to certain stimuli, these cells develop an enhanced secondary response with increased cytokine secretion even after an encounter with an unrelated stimulus. This phenomenon has been termed trained innate immunity (TI) and is associated with epigenetic modifications (histone methylation, acetylation) and metabolic alterations (elevated glycolysis, lactate production). TI has been observed in tissue-resident or circulating immune cells but also in bone marrow progenitors. Risk-factors for cardiovascular diseases (CVDs) which are associated with low-grade inflammation, such as hyperglycemia, obesity, or high salt, can also induce TI with a profound impact on the development and progression of CVDs. In this review, we briefly describe basic mechanisms of TI and summarize animal studies which specifically focus on TI in the context of CVDs

Factor Xa Inhibitors for Patients after Mechanical Heart Valve Replacement?

Patients with a mechanical heart valve need a lifelong anticoagulation due to the increased risk of valve thrombosis and thrombo-embolism. Currently, vitamin K antagonists (VKA) are the only approved class of oral anticoagulants, but relevant interactions and side effects lead to a large number of patients not achieving the optimal therapeutic target international normalized ration (INR). Therefore, steady measurements of the INR are imperative to ensure potent anticoagulation within a distinctive range. Direct oral anticoagulants (DOACs) with newer agents could serve as a possible alternative to VKAs in this patient cohort. DOACs are approved for several indications, e.g., atrial fibrillation (AF). They only have a minor interaction potential, which is why monitoring is not needed. Thereby, DOACs improve the livability of patients in need of chronical anticoagulation compared with VKAs. In contrast to dual platelet inhibition using aspirin in combination with an ADP receptor antagonist and the direct thrombin inhibitor dabigatran, the oral factor Xa inhibitors apixaban and rivaroxaban show promising results according to current evidence. In small-scale studies, factor Xa inhibitors were able to prevent thrombosis and thrombo-embolic events in patients with mechanical heart valves. Finally, DOACs seem to represent a feasible treatment option in patients with mechanical heart valves, but further studies are needed to evaluate clinical safety. In addition to the ongoing PROACT Xa trial with apixaban in patients after aortic On-X valve implantation, studies in an all-comer collective with rivaroxaban could be promising

Protective Effects of Curcumin in Cardiovascular Diseases—Impact on Oxidative Stress and Mitochondria

Cardiovascular diseases (CVDs) contribute to a large part of worldwide mortality. Similarly, two of the major risk factors for these diseases, aging and obesity, are also global problems. Aging, the gradual decline of body functions, is non-modifiable. Obesity, a modifiable risk factor for CVDs, also predisposes to type 2 diabetes mellitus (T2DM). Moreover, it affects not only the vasculature and the heart but also specific fat depots, which themselves have a major impact on the development and progression of CVDs. Common denominators of aging, obesity, and T2DM include oxidative stress, mitochondrial dysfunction, metabolic abnormalities such as altered lipid profiles and glucose metabolism, and inflammation. Several plant substances such as curcumin, the major active compound in turmeric root, have been used for a long time in traditional medicine and for the treatment of CVDs. Newer mechanistic, animal, and human studies provide evidence that curcumin has pleiotropic effects and attenuates numerous parameters which contribute to an increased risk for CVDs in aging as well as in obesity. Thus, curcumin as a nutraceutical could hold promise in the prevention of CVDs, but more standardized clinical trials are required to fully unravel its potential

B cell receptor-induced growth arrest and apoptosis in WEHI-231 immature B lymphoma cells involve cyclic AMP and Epac proteins

Signaling by the B cell antigen receptor (BCR) is essential for B lymphocyte homeostasis and immune function. In immature B cells, ligation of the BCR promotes growth arrest and apoptosis, and BCR-driven balancing between pro-apoptotic extracellular signal-regulated kinase 1 and 2 (ERK1/2) and antiapoptotic phosphoinositide 3-kinase-dependent Akt seems to define the final cellular apoptotic response. Dysfunction of these late BCR signaling events can lead to the development of immunological diseases. Here we report on novel cyclic AMP-dependent mechanisms of BCR-induced growth arrest and apoptosis in the immature B lymphoma cell line WEHI-231. BCR signaling to ERK1/2 and Akt requires cyclic AMP-regulated Epac, the latter acting as a guanine nucleotide exchange factor for Rap1 and H-Ras independent of protein kinase A. Importantly, activation of endogenously expressed Epac by a specific cyclic AMP analog enhanced the induction of growth arrest (reduced DNA synthesis) and apoptosis (nuclear condensation, annexin V binding, caspase-3 cleavage and poly-ADP-ribose polymerase processing) by the BCR. Our data indicate that cyclic AMP-dependent Epac signals to ERK1/2 and Akt upon activation of Rap1 and H-Ras, and is involved in BCR-induced growth arrest and apoptosis in WEHI-231 cells. (C) 2009 Elsevier Inc. All rights reserved

The Proteoglycan Biglycan Modulates Platelet Adhesion and Thrombus Formation in a GPVI-Dependent Manner

Background: Vascular injury induces the exposure of subendothelial extracellular matrix (ECM) important to serve as substrate for platelets to adhere to the injured vessel wall to avoid massive blood loss. Different ECM proteins are known to initiate platelet adhesion and activation. In atherosclerotic mice, the small, leucine-rich proteoglycan biglycan is important for the regulation of thrombin activity via heparin cofactor II. However, nothing is known about the role of biglycan for hemostasis and thrombosis under nonatherosclerotic conditions. Methods: The role of biglycan for platelet adhesion and thrombus formation was investigated using a recombinant protein and biglycan knockout mice. Results: The present study identified biglycan as important ECM protein for the adhesion and activation of platelets, and the formation of three-dimensional thrombi under flow conditions. Platelet adhesion to immobilized biglycan induces the reorganization of the platelet cytoskeleton. Mechanistically, biglycan binds and activates the major collagen receptor glycoprotein (GP)VI, because reduced platelet adhesion to recombinant biglycan was observed when GPVI was blocked and enhanced tyrosine phosphorylation in a GPVI-dependent manner was observed when platelets were stimulated with biglycan. In vivo, the deficiency of biglycan resulted in reduced platelet adhesion to the injured carotid artery and prolonged bleeding times. Conclusions: Loss of biglycan in the vessel wall of mice but not in platelets led to reduced platelet adhesion at the injured carotid artery and prolonged bleeding times, suggesting a crucial role for biglycan as ECM protein that binds and activates platelets via GPVI upon vessel injury

CD73 deficiency does not aggravate angiotensin II-induced aortic inflammation in mice

Abstract Vascular inflammation plays a key role in the development of aortic diseases. A potential novel target for treatment might be CD73, an ecto-5′-nucleotidase that generates anti-inflammatory adenosine in the extracellular space. Here, we investigated whether a lack of CD73 results in enhanced aortic inflammation. To this end, angiotensin II was infused into wildtype and CD73−/− mice over 10 days. Before and after infusion, mice were analyzed using magnetic resonance imaging, ultrasound, flow cytometry, and histology. The impact of age and gender was investigated using female and male mice of three and six months of age, respectively. Angiotensin II infusion led to increased immune cell infiltration in both genotypes’ aortae, but depletion of CD73 had no impact on immune cell recruitment. These findings were not modified by age or sex. No substantial difference in morphological or functional characteristics could be detected between wildtype and CD73−/− mice. Interestingly, the expression of CD73 on neutrophils decreased significantly in wildtype mice during treatment. In summary, we have found no evidence that CD73 deficiency affects the onset of aortic inflammation. However, as CD73 expression decreased during disease induction, an increase in CD73 by pharmaceutical intervention might result in lower vascular inflammation and less vascular disease