Doxycycline induces mitochondrial dysfunction in aortic smooth muscle cells.

The antibiotic doxycycline is known to inhibit inflammation and was therefore considered as a therapeutic to prevent abdominal aortic aneurysm (AAA) growth. Yet mitochondrial dysfunction is a key-characteristic of clinical AAA disease. We hypothesize that doxycycline impairs mitochondrial function in the aorta and aortic smooth muscle cells (SMCs). Doxycycline induced mitonuclear imbalance, reduced proliferation and diminished expression of typical contractile smooth muscle cell (SMC) proteins. To understand the underlying mechanism, we studied krüppel-like factor 4 (KLF4). The expression of this transcription factor was enhanced in SMCs after doxycycline treatment. Knockdown of KLF4, however, did not affect the doxycycline-induced SMC phenotypic changes. Then we used the bioenergetics drug elamipretide (SS-31). Doxycycline-induced loss of SMC contractility markers was not rescued, but mitochondrial genes and mitochondrial connectivity improved upon elamipretide. Thus while doxycycline is anti-inflammatory, it also induces mitochondrial dysfunction in aortic SMCs and causes SMC phenotypic switching, potentially contributing to aortic aneurysm pathology. The drug elamipretide helps mitigate the harmful effects of doxycycline on mitochondrial function in aortic SMC, and may be of interest for treatment of aneurysm diseases with pre-existing mitochondrial dysfunction.

Six Shades of Vascular Smooth Muscle Cells Illuminated by KLF4 (Krüppel-Like Factor 4).

Multiple layers of vascular smooth muscle cells (vSMCs) are present in blood vessels forming the media of the vessel wall. vSMCs provide a vessel wall structure, enabling it to contract and relax, thus modulating blood flow. They also play a crucial role in the development of vascular diseases, such as atherosclerosis and aortic aneurysm formation. vSMCs display a remarkable high degree of plasticity. At present, the number of different vSMC phenotypes has only partially been characterized. By mapping vSMC phenotypes in detail and identifying triggers for phenotype switching, the relevance of the different phenotypes in vascular disease may be identified. Up until recently, vSMCs were classified as either contractile or dedifferentiated (ie, synthetic). However, single-cell RNA sequencing studies revealed such dedifferentiated arterial vSMCs to be highly diverse. Currently, no consensus exist about the number of vSMC phenotypes. Therefore, we reviewed the data from relevant single-cell RNA sequencing studies, and classified a total of 6 vSMC phenotypes. The central dedifferentiated vSMC type that we classified is the mesenchymal-like phenotype. Mesenchymal-like vSMCs subsequently seem to differentiate into fibroblast-like, macrophage-like, osteogenic-like, and adipocyte-like vSMCs, which contribute differentially to vascular disease. This phenotype switching between vSMCs requires the transcription factor KLF4 (Kruppel-like factor 4). Here, we performed an integrated analysis of the data about the recently identified vSMC phenotypes, their associated gene expression profiles, and previous vSMC knowledge to better understand the role of vSMC phenotype transitions in vascular pathology.

Microbial metabolism of L-tyrosine protects against allergic airway inflammation.

The constituents of the gut microbiome are determined by the local habitat, which itself is shaped by immunological pressures, such as mucosal IgA. Using a mouse model of restricted antibody repertoire, we identified a role for antibody-microbe interactions in shaping a community of bacteria with an enhanced capacity to metabolize L-tyrosine. This model led to increased concentrations of p-cresol sulfate (PCS), which protected the host against allergic airway inflammation. PCS selectively reduced CCL20 production by airway epithelial cells due to an uncoupling of epidermal growth factor receptor (EGFR) and Toll-like receptor 4 (TLR4) signaling. Together, these data reveal a gut microbe-derived metabolite pathway that acts distally on the airway epithelium to reduce allergic airway responses, such as those underpinning asthma.

Immunomodulation in Heart Failure with Preserved Ejection Fraction: Current State and Future Perspectives.

The heart failure (HF) epidemic is growing and approximately half of the HF patients have heart failure with preserved ejection fraction (HFpEF). HFpEF is a heterogeneous syndrome, characterized by a preserved left ventricular ejection fraction (LVEF ≥ 50%) with diastolic dysfunction, and is associated with high morbidity and mortality. Underlying comorbidities of HFpEF, i.e., hypertension, type 2 diabetes mellitus, obesity, and renal failure, lead to a systemic pro-inflammatory state, thereby affecting normal cardiac function. Increased inflammatory biomarkers predict incident HFpEF and are higher in patients with HFpEF as compared with heart failure with reduced ejection fraction (HFrEF). Randomized trials in HFpEF patients using traditional HF medication failed to demonstrate a clear benefit on hard endpoints (mortality and/or HF hospitalization). Therefore, therapies targeting underlying comorbidities and systemic inflammation in early HFpEF may provide better opportunities. Here, we provide an overview of the current state and future perspectives of immunomodulatory therapies for HFpEF.

HIV knowledge, sexual health and sexual behaviour among Black and minority ethnic men who have sex with men in the UK: a cross-sectional study.

Background Black and minority ethnic (BME) men who have sex with men (MSM) face a major burden in relation to HIV infection. Using a cross-sectional correlational survey design, the present study explored the relationships between HIV knowledge and reported sexual health and sexual behaviour in this population. METHODS: A convenience sample of 538 BME MSM was recruited in London, Leicester and Leeds: 346 (64%) self-identified as South Asian, 88 (16%) self-identified as Latin American, 76 (14%) self-identified as Black, 13 (2%) self-identified as mixed, and 15 (3%) self-identified as other. RESULTS: HIV knowledge was low across the board, and South Asian MSM manifested the lowest scores. Respondents who perceived their HIV risk to be low possessed the least HIV knowledge. There were interethnic differences in the frequency of gay sauna visits, sex-seeking on mobile applications, drug use and attendance at sex parties. Respondents reported a high frequency of racism and discrimination, with Black MSM reporting highest frequency. CONCLUSIONS: There is an urgent need to raise awareness of HIV in BME MSM, and a culturally competent approach to HIV awareness-raising in BME MSM is required. These findings shed light on the contexts in which HIV prevention efforts should be targeted to reach specific ethnic groups, as well as some of the potential syndemics that can increase HIV risk or undermine HIV outcomes in BME MSM patients.