CRIF1 attenuates doxorubicin-mediated mitochondrial dysfunction and myocardial senescence via regulating PXDN.

BACKGROUND: CR6-interacting factor 1 (CRIF1), a multifunctional protein that affects mitochondrial function and cell senescence, plays a regulatory role in heart-related diseases. However, whether CRIF1 participates in myocardial senescence by regulating mitochondrial function remains unclear. METHODS: Doxorubicin (DOX)-induced C57BL/6 mice to construct mouse myocardial senescence model, and the myocardial function indicators including lactate dehydrogenase (LDH) and Creatine kinase isoform MB (CK-MB) were assessed. The expression of CRIF1 was detected by western blot. Myocardial pathological changes were examined by transthoracic echocardiography and haematoxylin and eosin (H&E) staining. Cell senescence was detected by SA-ß-gal staining. JC-1 staining was used to detect mitochondrial membrane potential. Biochemical kits were used to examine oxidative stress-related factors. Additionally, AC16 cardiomyocytes were treated with DOX to mimic the cellular senescence model in vitro. Cell activity was detected by cell counting kit-8 (CCK-8) assay. Co-immunoprecipitation (CO-IP) was used to verify the relationship between CRIF1 and peroxidasin (PXDN). RESULTS: The CRIF1 expression was significantly decreased in DOX-induced senescent mice and AC16 cells. Overexpression of CRIF1 significantly ameliorated DOX-induced myocardial dysfunction and myocardial senescence. Additionally, CRIF1 overexpression attenuated DOX-induced oxidative stress and myocardial mitochondrial dysfunction. Consistently, CRIF1 overexpression also inhibited DOX-induced oxidative stress and senescence in AC16 cells. Moreover, CRIF1 was verified to bind to PXDN and inhibited PXDN expression. The inhibitory effects of CRIF1 overexpression on DOX-induced oxidative stress and senescence in AC16 cells were partly abolished by PXDN expression. CONCLUSIONS: CRIF1 plays a protective role against DOX-caused mitochondrial dysfunction and myocardial senescence partly through downregulating PXDN.

[A study of the relationship between remodeling of left ventricle and endothelial injury and pro-inflammatory mediators in different stages of essential hypertension].

OBJECTIVE: To explore the relationship between left ventricular remodeling and vascular endothelial injury and pro-inflammatory mediators in different stages of essential hypertension. METHODS: Patients were grouped in according to the duration of the disease. The control group consisted of patients with history of hypertension for 6 months to 1 year (35 cases), patients with a history of 3 years were categorized as group A (38 cases), patients with 5-year history as group B (32 cases), 8-year history as group C (33 cases), 13-year history as group D (34 cases), 15-year history as group E (32 cases). Ultrasonic measurements included left atrial diameter (LAD), interventricular septal thickness (IVST), left ventricular posterior wall thickness (PWT). Nitric oxide (NO, nitrate reductase method), plasma endothelin-1 (ET-1, radioimmunoassay), tumor necrosis factor-alpha (TNF-alpha, radioimmunoassay), high-sensitivity C-reactive protein (hs-CRP, turbidimetry method) and interleukin-6 (IL-6, enzyme linked immunosorbent assay) were determined. RESULTS: There was no significant difference in ultrasonic measurements, vascular endothelial function and pro-inflammatory factors between control group and group A (all P>0.05). With prolongation of disease, there was obvious change in left ventricular remodeling, and the level of NO lowered, but the levels of ET-1, hs-CRP, TNF-alpha, IL-6 were elevated (F(LAD)=5.89, F(IVST)=6.58, F(PWT)=9.84, F(NO)=7.58, F(ET-1)=6.21, F( hs-CRP)=9.80, lzF(TNF-alpha)=12.45, F(IL-6)=6.53, all P<0.01). Compared with the control group, LAD, IVST, PWT, and the levels of NO, ET-1, hs-CRP, TNF-alpha, IL-6 showed statistically significant differences (P<0.05 or P<0.01). There were significant differences among groups B, C, D and E when compared one another (all P<0.01). CONCLUSION: The longer the duration of essential hypertension, the more obvious changes are found in left ventricular remodeling and endothelial injury. Pro-inflammatory factors promote endothelial injury and left ventricular remodeling. The vascular endothelial injury and pro-inflammatory mediators are the main promoters of atherosclerosis.