Dipeptidyl peptidase-4 disturbs adipocyte differentiation via the negative regulation of the glucagon-like peptide-1/adiponectin-cathepsin K axis in mice under chronic stress conditions.

Exposure to chronic psychosocial stress is a risk factor for metabolic disorders. Because dipeptidyl peptidase-4 (DPP4) and cysteinyl cathepsin K (CTSK) play important roles in human pathobiology, we investigated the role(s) of DPP4 in stress-related adipocyte differentiation, with a focus on the glucagon-like peptide-1 (GLP-1)/adiponectin-CTSK axis in vivo and in vitro. Plasma and inguinal adipose tissue from non-stress wild-type (DPP4+/+), DPP4-knockout (DPP4-/-) and CTSK-knockout (CTSK-/-) mice, and stressed DPP4+/+, DPP4-/-, CTSK-/-, and DPP4+/+ mice underwent stress exposure plus GLP-1 receptor agonist exenatide loading for 2 weeks and then were analyzed for stress-related biological and/or morphological alterations. On day 14 under chronic stress, stress decreased the weights of adipose tissue and resulted in harmful changes in the plasma levels of DPP4, GLP-1, CTSK, adiponectin, and tumor necrosis factor-α proteins and the adipose tissue levels of CTSK, preadipocyte factor-1, fatty acid binding protein-4, CCAAT/enhancer binding protein-α, GLP-1 receptor, peroxisome proliferator-activated receptor-γ, perilipin2, secreted frizzled-related protein-4, Wnt5α, Wnt11 and ß-catenin proteins and/or mRNAs as well as macrophage infiltration in adipose tissue; these changes were rectified by DPP4 deletion. GLP-1 receptor activation and CTSK deletion mimic the adipose benefits of DPP4 deficiency. In vitro, CTSK silencing and overexpression respectively prevented and facilitated stress serum and oxidative stress-induced adipocyte differentiation accompanied with changes in the levels of pref-1, C/EBP-α, and PPAR-γ in 3T3-L1 cells. Thus, these findings indicated that increased DPP4 plays an essential role in stress-related adipocyte differentiation, possibly through a negative regulation of GLP-1/adiponectin-CTSK axis activation in mice under chronic stress conditions.

Duchenne muscular dystrophy involves the myocardium and causes arrhythmia: Case report.

Background: Patients with muscular dystrophy have mutations in the gene that can lead to severe muscle wasting, respiratory issues or heart failure between ages 30 and 40. Currently, there is no effective treatment for DMD-induced heart failure. Case presentation: We report a patient with recurrent unexplained fever and muscle soreness was definitely diagnosed with DMD. An analysis of the patient's genetics revealed a nonsense mutation (C.1207G > T). His DMD was treated with hormones. Also, the patient's fever is under control because of hormone therapy. However, as the disease progresses, the heart structure and function gradually change, and eventually malignant arrhythmias occur. Conclusion: We report a rare case of DMD involving the heart causing heart failure and malignant arrhythmia. Currently, no complete treatment is available for these patients, but our treatment regimen may benefit our patient and improve his outcomes.

Successful ablation of a left anterior accessory pathway from the left coronary sinus of Valsalva near the aortic-mitral continuity.

Catheter ablation of accessory pathways can be challenging depending on the location of these pathways, and accessory pathways are rare through the aortic cusps. We report a patient who underwent radiofrequency catheter ablation for manifestation of a left anterior accessory pathway from the left coronary sinus of Valsalva near the aortic-mitral continuity. Anterior accessory pathways can be safely and effectively ablated from the aortic cusps with favorable long-term outcomes.

FBXW5 acts as a negative regulator of pathological cardiac hypertrophy by decreasing the TAK1 signaling to pro-hypertrophic members of the MAPK signaling pathway.

Pathological cardiac hypertrophy is a crucial cause of cardiac morbidity and mortality worldwide. However, the molecular mechanisms of this disease remain incompletely understood. As a member of E3 ubiquitin ligases, F-box/WD repeat-containing protein 5 (FBXW5) has been implicated in various pathophysiological processes. However, the role of FBXW5 in pathological cardiac hypertrophy remains largely unknown. In this study, decreased expression of FBXW5 was observed in both neonatal rat cardiomyocytes and mouse hearts with hypertrophic remodeling. Gain- and loss-of-function experiments were performed to study the potential function of FBXW5 in pathological cardiac hypertrophy. The in vitro results showed that FBXW5 had a protective effect against cardiac hypertrophy induced by phenylephrine (PE). FBXW5 knockout mice and mice with AAV9-mediated FBXW5 overexpression were generated. Consistent with the in vitro results, FBXW5 deficiency aggravated cardiac hypertrophy induced by pressure overload. FBXW5 overexpression protected mice from hypertrophic stimuli. Remarkably, FBXW5 ameliorated pathological cardiac hypertrophy by directly interacting with the protein transforming growth factor-beta-activated kinase 1 (TAK1) and blocking the mitogen-activated protein kinase (MAPK) signaling pathway. Furthermore, inhibition of TAK1 prevented the effects of FBXW5 on agonist- or pressure overload-induced cardiac hypertrophy. These findings imply that FBXW5 is an essential negative regulator and may be a potential therapeutic target for pathological cardiac hypertrophy.

Novel Role for Pleckstrin Homology-Like Domain Family A, Member 3 in the Regulation of Pathological Cardiac Hypertrophy.

Background Pleckstrin homology-like domain family A, member 3 (PHLDA3), a crucial member of the PHLDA family, is involved in tumor suppression, kidney injury, liver injury, and glucose metabolism. However, the role of PHLDA3 in pathological cardiac hypertrophy and heart failure remains unclear. Methods and Results In the present study, PHLDA3 expression was downregulated in hypertrophic murine hearts and angiotensin II-treated cardiomyocytes. Next, an in vitro study suggested, by using gain- and loss-of-function approaches, that PHLDA3 attenuates Ang II exposure-induced cardiomyocyte hypertrophy. Consistent with the cell phenotype, disruption of PHLDA3 aggravated the effects of pressure overload-induced pathological cardiac hypertrophy, fibrosis, and dysfunction. In contrast, PHLDA3 overexpression resulted in an attenuated hypertrophic phenotype. Molecular analysis revealed that PHLDA3 suppressed the activation of AKT-mTOR-GSK3ß-P70S6K signaling in response to hypertrophic stress, and the blockage of AKT activation rescued these adverse pathological effects of PHLDA3 deficiency-induced by AB and Ang II, respectively, in vivo and in vitro. Conclusions Collectively, our data indicated that PHLDA3 could ameliorate pressure overload-induced cardiac remodeling mainly by blocking the AKT signaling pathway, suggesting that PHLDA3 may represent a therapeutic target for the treatment of pathological cardiac hypertrophy and heart failure.

Monoamine oxidase inhibitors protect against coronary heart disease in rodent rat models: A pilot study.

The present study designed to investigate the effect of monoamine oxidase inhibitor in the rat model of Coronary heart disease (cardiac hypertrophy). A total of 40 male adult Wistar rats having body weight 300-400 gram were equally distributed in two groups (Test group: Rats with Angiotensin II + monoamine oxidase inhibitor (Befloxatone); Reference group: Rats with cardiac hypertrophy induced by Angiotensin II). Rat model of cardiac hypertrophy were induced by Angiotensin II. Effect of Befloxatone on cardiac hypertrophy was evaluated by electrocardiography, hemodynamic and histological assessment. Vital signs such as pulse rate, and blood pressure were measured. Echocardiographic related variable including ejection fraction were also assessed in both the groups. Also, expression of monoamine oxidase was analyzed using by real-time-PCR and Western blot analysis. In results, we found following 1) monoamine oxidase inhibitor treatment prevents Angiotensin II induced increase in level of ANP and ßeta-myosin, which are responsible for inducing cardiac hypertrophic responses; 2) monoamine oxidase inhibitor ameliorates Angiotensin II induced cell enlargement by reducing the surface area of cells; 3) monoamine oxidase inhibitor attenuates the hypertrophic response triggered by Angiotensin II; 4) monoamine oxidase inhibitor ameliorates increased heart rate and average arterial pressure induced by angiotensin II; 5) Overall finding suggested that monoamine oxidase inhibitor improves left ventricle hypertrophy and ejection fraction by inhibiting monoamine oxidase enzyme in heart. The finding of this study gives the new vision to cardiovascular researchers to develop anti- hypertrophy therapy based on monoamine oxidase inhibition.