Mitochondrial DNA (mtDNA) damage is associated with the development of cardiovascular diseases. Cardiac aging plays a central role in cardiovascular diseases. There is accumulating evidence linking cardiac aging to mtDNA damage, including mtDNA mutation and decreased mtDNA copy number. Current wisdom indicates that mtDNA is susceptible to damage by mitochondrial reactive oxygen species (mtROS). This review presents the cellular and molecular mechanisms of cardiac aging, including autophagy, chronic inflammation, mtROS, and mtDNA damage, and the effects of mitochondrial biogenesis and oxidative stress on mtDNA. The importance of nucleoid-associated proteins (Pol γ), nuclear respiratory factors (NRF1 and NRF2), the cGAS-STING pathway, and the mitochondrial biogenesis pathway concerning the development of mtDNA damage during cardiac aging is discussed. Thus, the repair of damaged mtDNA provides a potential clinical target for preventing cardiac aging.

No abstract

Neuronal signaling together with synapse activity in the central nervous system requires a precisely regulated microenvironment. Recently, the blood-brain barrier is considered as a “neuro-glia-vascular unit,” a structural and functional compound composed of capillary endothelial cells, glial cells, pericytes, and neurons, which plays a pivotal role in maintaining the balance of the microenvironment in and out of the brain. Tight junctions and adherens junctions, which function as barriers of the blood-brain barrier, are two well-known kinds in the endothelial cell junctions. In this review, we focus on the less-concerned contribution of gap junction proteins, connexins in blood-brain barrier integrity under physio-/pathology conditions. In the neuro-glia-vascular unit, connexins are expressed in the capillary endothelial cells and prominent in astrocyte endfeet around and associated with maturation and function of the blood-brain barrier through a unique signaling pathway and an interaction with tight junction proteins. Connexin hemichannels and connexin gap junction channels contribute to the physiological or pathological progress of the blood-brain barrier; in addition, the interaction with other cell-cell-adhesive proteins is also associated with the maintenance of the blood-brain barrier. Lastly, we explore the connexins and connexin channels involved in the blood-brain barrier in neurological diseases and any programme for drug discovery or delivery to target or avoid the blood-brain barrier.

Mitofusin-2 (Mfn2) is a key outer mitochondrial membrane protein, which maintains normal mitochondrial dynamics and function. However, its role in cardiac fibroblast activation remains poorly understood. In the present study, a rat model of transverse aortic constriction (TAC) was established to observe the cardiac fibroblast activation in vivo. TGF-β1 treatment for 24 hours was used to induce cardiac fibroblast activation in vitro. As a result, the expression of Mfn2 decreased in the hypertrophic heart tissues and cardiac fibroblasts treated with TGF-β1. siMfn2 and adenovirus were applied to mediate Mfn2 gene silencing and overexpression in cardiac fibroblasts to elucidate the relationship between Mfn2 and cardiac fibroblast activation, as well as the possible underlying mechanisms. Knockdown of Mfn2 further promoted TGF-β1-induced cardiac fibroblast activation, while forced expression of Mfn2 attenuated this pathological reaction. The PERK/ATF4 pathway, one of the branches of endoplasmic reticulum (ER) stress, was identified to be involved in this process. Knockdown and overexpression of Mfn2 lead to aggravation or alleviation of the PERK/ATF4 pathway. Blocking this pathway by silencing ATF4 with siATF4 attenuated the pathological process. During the activation of cardiac fibroblasts, knockdown of Mfn2 also increased the production of reactive oxygen species (ROS), while ROS scavenger N-acetyl-l-cysteine (NAC) could attenuate the effect caused by knockdown of Mfn2. Our data suggested that inhibition of Mfn2 could promote cardiac fibroblast activation by activating the PERK/ATF4 signaling pathway and increasing the generation of ROS.

No abstract

Background: Calcium (Ca 2+ ) is a key regulator of energy metabolism. Impaired Ca 2+ homeostasis damages mitochondria, causing cardiomyocyte death, pathological hypertrophy, and heart failure. This study investigates the regulation and the role of the mitochondrial Ca 2+ uniporter (MCU) in chronic stress-induced pathological cardiac remodeling. Methods: MCU knockout or transgenic mice were infused with isoproterenol (ISO, 10 mg/kg/day, 4 weeks). Cardiac hypertrophy and remodeling were evaluated by echocardiography and histology. Primary cultured rodent adult cardiomyocytes were treated with ISO (1 nM, 48 hr). Intracellular Ca 2+ handling and cell death pathways were monitored. Adenovirus-mediated gene manipulations were used in vitro . Results: Chronic administration of the β-adrenergic receptor (β-AR) agonist ISO increased the levels of the MCU and the MCU complex in cardiac mitochondria, raising mitochondrial Ca 2+ concentrations, in vivo and in vitro . ISO also upregulated MCU without affecting its regulatory proteins in adult cardiomyocytes. Interestingly, ISO-induced cardiac hypertrophy, fibrosis, contractile dysfunction, and cardiomyocyte death were exacerbated in global MCU knockout (KO) mice. Cardiomyocytes from KO mice or mice overexpressing a dominant negative MCU exhibited defective intracellular Ca 2+ handling and activation of multiple cell death pathways. Conversely, cardiac-specific overexpression of MCU maintained intracellular Ca 2+ homeostasis and contractility, suppressed cell death, and prevented ISO-induced heart hypertrophy. ISO upregulated MCU expression through activation of Ca 2+ /calmodulin kinase II δB (CaMKIIδB) and promotion of its nuclear translocation via calcineurin-mediated dephosphorylation at serine 332. Nuclear CaMKIIδB phosphorylated cAMP-response element binding protein (CREB), which bound the MCU promotor to enhance MCU gene transcription. Conclusions: The β-AR/CaMKIIδB/CREB pathway upregulates MCU gene expression in the heart. MCU upregulation is a compensatory mechanism that counteracts stress-induced pathological cardiac remodeling by preserving Ca 2+ homeostasis and cardiomyocyte viability.

No abstract

BackgroundChronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most commonly observed phenotype among chronic acquired demyelinating polyneuropathies and is clinically variable. The aim of this meta‐analysis was to evaluate the diagnostic value and characteristics of CIDP targeting neurofascin 155 (NF155).MethodsA systematic literature search was performed on March 2018, and two reviewers independently extracted data and assessed the risk of bias on MEDLINE, EMBASE, the Web of Science, and the Cochrane Library to identify relevant articles.ResultsTen articles for the NF155 protein test with 1,161 patients and 1,636 controls were identified. The results showed that the pooled sensitivity was 0.09 (95% CI: 0.06–015), and specificity was 1.00 (95% CI: 0.98–1.00) of the NF155 for CIDP. The meta‐analysis revealed that the sensory ataxic occurrence rate (OR: 10.79, 95% CI: 5.24–22.22) and tremor occurrence rate (OR: 6.71, 95% CI: 3.37–13.39) were higher among patients positive for NF155 compared with NF155‐negative CIDP patients. However, the rate of good treatment response to intravenous immunoglobulin (IVIg) (OR: 0.09, 95% CI: 0.02–0.42) was lower in NF155‐positive CIDP patients.ConclusionsNF155 is a specific protein marker for CIDP, but its diagnostic value has been questioned due to low sensitivity. However, as an antibody against paranodal antigens, NF155 seems more valuable in defining clinical subsets of CIDP.