Effect of imatinib on DOCA-induced myocardial fibrosis in rats through P38 MAPK signaling pathway.

OBJECTIVE: To explore the role of imatinib in desoxycorticosterone acetate (DOCA)-induced myocardial fibrosis in rats by the p38 mitogen-activated protein kinase (MAPK) signaling pathway. MATERIALS AND METHODS: Normal group (n=20), DOCA induction group (n=20), and imatinib treatment group (treatment group, n=20) were set up. Then, the cardiac function was examined via magnetic resonance imaging (MRI) and echocardiography (ECG) on the 21st d after modeling. Alkaline phosphatase (ALP) and myocardial function index creatine kinase-MB (CK-MB) were detected. The enzyme-linked immunosorbent assay (ELISA) was performed to measure tumor necrosis factor-gamma (TNF-γ) and interleukin-6 (IL-6). Hematoxylin-eosin (HE) staining assay was carried out to observe the pathological changes in myocardial tissues. Quantitative Polymerase Chain Reaction (qPCR) and Western blotting were employed to measure the expression levels of important myocardial fibrosis-related genes [checkpoint kinase 1 (Chek1) and alpha-smooth muscle actin (α-SMA)], as well as genes and proteins of the p38 MAPK signaling pathway. RESULTS: In comparison with the normal group, DOCA induction group had significantly lowered fractional shortening (FS, %) and ejection fraction (EF, %), but overtly increased left ventricular end-diastolic dimension (LVEDd) and left ventricular end-systolic dimension (LVESd), as well as levels of serum ALP, alanine aminotransferase (ALT), and CK-MB. Besides, the levels of TNF-γ, IL-6, and IL-1ß were notably raised in the DOCA induction group. HE staining results showed that myocardial injury was more severe in DOCA induction group. The results of the gene detection revealed that the expression levels of Chek1, α-SMA, p38 MAPK, and JNK were evidently higher in DOCA induction group than those in the imatinib treatment group (p<0.05), and the expression of p38 MAPK protein in the rat myocardial tissues was remarkably lower in the treatment group than that in the DOCA induction group (p<0.05). CONCLUSIONS: Imatinib can regulate the repair of myocardial injury caused by DOCA-induced myocardial fibrosis in rats by repressing the p38 MAPK signaling pathway.

Collecting Duct Renin Does Not Mediate DOCA-Salt Hypertension or Renal Injury.

Collecting duct (CD)-derived renin is involved in the hypertensive response to chronic angiotensin-II (Ang-II) administration. However, whether CD renin is involved in Ang-II independent hypertension is currently unknown. To begin to examine this, 12 week old male and female CD-specific renin knock out (KO) mice and their littermate controls were subjected to uni-nephrectomy followed by 2 weeks of deoxycorticosterone acetate (DOCA) infusion combined with a high salt diet. Radiotelemetric blood pressure (BP) was similar between KO and control mice at baseline; BP increased in both groups to a similar degree throughout the 2 weeks of DOCA-salt treatment. Urinary albumin excretion and plasma blood urea nitrogen were comparable between the two groups after DOCA-salt treatment. Fibrosis as assessed by Masson's Trichrome stain/Sirius Red stain and collagen-1 mRNA expression was similar between control and KO mice. Compared to baseline, DOCA-salt treatment decreased plasma renin concentration (PRC), urinary renin excretion and medullary renin mRNA expression in both floxed and CD renin KO mice with no detectable differences between the two groups. Further, in primary culture of rat inner medullary CD, aldosterone treatment did not change renin activity or total renin content. Taken together, these data suggest that CD derived renin does not play a role in DOCA-salt hypertension.