UCHL1 positively regulates cardiac hypertrophy via stabilizing EGFR and highlighting it as a yet unknown therapeutic target.

Background: The recruitment of leukocytes to the vascular wall is a key step in hypertension development. Chemokine receptor CXCR2 mediates inflammatory cell chemotaxis in several diseases. However, the role of CXCR2 in hypertension development and the underlying mechanisms remain unknown. Methods: Angiotensin II (490 ng·kg ^-1 ·min ^-1 ) or deoxycorticosterone acetate (DOCA) salt–induced mouse hypertensive models in genetic ablation, pharmacologic inhibition of CXCR2, and adoptive bone marrow transfer mice were used to determine the role of CXCR2 in hypertension (measured by radiotelemetry and tail-cuff system), inflammation (verified by flow cytometry and quantitative real-time polymerase chain reaction [PCR] analysis), vascular remodeling (studied by haematoxylin and eosin and Masson’s trichrome staining), vascular dysfunction (assessed by aortic ring), and oxidative stress (indicated by nicotinamide adenine dinucleotide phosphate [NADPH] oxidase activity, dihydroethidium staining, and quantitative real-time PCR analysis). Moreover, the blood CXCR2 ⁺ cells in normotensive controls and hypertension patients were analyzed by flow cytometry. Results: Angiotensin II significantly upregulated the expression of CXCR2 mRNA and protein and increased the number of CD45 ⁺ CXCR2 ⁺ cells in mouse aorta (n=8 per group). Selective CXCR2 knockout (CXCR2 ^-/- ) or pharmacological inhibition of CXCR2 markedly reduced angiotensin II- or DOCA-salt-induced blood pressure elevation, aortic thickness and collagen deposition, accumulation of proinflammatory cells into the vascular wall, and expression of cytokines (n=8 per group). CXCR2 inhibition also ameliorated angiotensin II-induced vascular dysfunction and reduced vascular superoxide formation, NADPH activity, and expression of NADPH oxidase subunits (n=6 per group). Bone marrow reconstitution of wild-type mice with CXCR2 ^-/- bone marrow cells also significantly abolished angiotensin II-induced responses (n=6 per group). It is important to note that CXCR2 blockade reversed established hypertension induced by angiotensin II or DOCA-salt challenge (n=10 per group). Furthermore, we demonstrated that CXCR2 ⁺ proinflammatory cells were higher in hypertensive patients (n=30) compared with normotensive individuals (n=20). Conclusions: Infiltration of CXCR2 ⁺ cells plays a pathogenic role in arterial hypertension and vascular dysfunction. Inhibition of CXCR2 pathway may represent a novel therapeutic approach to treat hypertension.

Angiotensin II stimulates fibroblast proliferation and substantially alters gene expression patterns leading to cardiac remodeling, but the mechanisms for such differences are unknown. MicroRNAs are a novel mechanism for gene expression regulation. Herein, we tested the miRNA and mRNA expression patterns in mouse heart using microarray assay and investigated their role in angiotensin II–induced cardiac remodeling. We found that let-7i was dynamically downregulated in angiotensin II–infused heart at day 3 and 7 and had the most targets that were mainly associated with cardiac inflammation and fibrosis. Overexpression or knockdown of let-7i in cultured cardiac fibroblasts demonstrated that let-7i played an inhibitory effect on the expression of its targets interleukin-6 and collagens. Furthermore, delivery of let-7i to mouse significantly inhibited angiotensin II–induced cardiac inflammation and fibrosis in a dose-dependent manner. Conversely, knockdown of let-7i aggravated this effect. Together, our results clearly demonstrate that let-7i acts as a novel negative regulator of angiotensin II–induced cardiac inflammation and fibrosis by suppressing the expression of interleukin-6 and multiple collagens in the heart and may represent a new potential therapeutic target for treating hypertensive cardiac fibrosis.

Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia that leads to numerous adverse outcomes including stroke, heart failure, and death. Hyperuricemia is an important risk factor that contributes to atrium injury and AF, but the underlying molecular mechanism remains to be elucidated. In this review, we discussed the scientific evidence for clarifying the role of hyperuricemia in the pathogenesis of AF. Experimental and Clinical evidence endorse hyperuricemia as an independent risk factor for the incidence of AF. Various in vivo and in vitro investigations showed that hyperuricemia might play a critical role in the pathogenesis of AF at different UA concentrations through the activation of oxidative stress, inflammation, fibrosis, apoptosis, and immunity.

Background: The association between dyslipidemia, a major risk factor for cardiovascular diseases, and atrial fibrillation (AF) is not clear because of limited evidence.Hypothesis.: Dyslipidemia may be associated with increased risk of AF in a Chinese population.Methods: A total of 88 785 participants free from AF at baseline (2006–2007) were identified from the Kailuan Study. Fasting levels of total cholesterol (TC), low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), and triglycerides (TG) were measured at baseline using standard procedures. The study population was stratified based on quartiles of lipid profile. Incident AF was ascertained from electrocardiograms at biennial follow‐up visits (2008–2015). The associations between incident AF and the different lipid parameters (TC, LDL‐C, HDL‐C, and TG) were assessed by Cox proportional hazards regression analysis.Results: Over a mean follow‐up period of 7.12 years, 328 subjects developed AF. Higher TC (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.43‐0.84) and LDL‐C (HR: 0.60, 95% CI: 0.43‐0.83) levels were inversely associated with incident AF after multivariable adjustment. HDL‐C and TG levels showed no association with newly developed AF. The results remained consistent after exclusion of individuals with myocardial infarction or cerebral infarction, or those on lipid‐lowering therapy. Both TC/HDL‐C and LDL‐C/HDL‐C ratios were inversely associated with risk of AF (per unit increment, HR: 0.88, 95% CI: 0.79‐0.98 and HR: 0.77, 95% CI: 0.66‐0.91, respectively).Conclusions: TC and LDL‐C levels were inversely associated with incident AF, whereas no significant association of AF with HDL‐C or TG levels was observed.