ABSTRACT
Myocardial hypertrophy is a pathological thickening of the myocardium, leading to various ailments, such as myocardial infarction and heart failure. RBM38 is critical in modulating mRNA translation for multiple protective activities such as p53 tumor repressor and p21 kinase cell cycle inhibitors. Liver X receptors (LXR-α) agonists reduce cellular hypertrophy initiated by various hypertrophic stimuli as lipopolysaccharides and Ang II. This research investigates the possible cooperation between RBM38 and LXR-α and mechanisms in modulating myocardial hypertrophy. H9C2 cells were treated with PE, TNF-α, and AngII to induce myocardial hypertrophy. RBM38 and LXR- α were overexpressed or silenced in H9C2 cells, and hypertrophy markers (ANF and Myh7) were determined with Western blot and RT-qPCR. Binding assays were done through RNA immunoprecipitation. H&E and Rhodamine-labeled phalloidin staining assays were used to assess the relative cell surface change. The results demonstrated RBM38 downregulation in in vitro models of myocardial hypertrophy. Modulation of RBM38 expression also exerted inverse effects on myocardial hypertrophy markers. Further observations also showed that LXR-α expression regulates the myocardial hypertrophy markers in H9C2 cells and RBM38 binds with LXR-α mRNA, consequently inhibiting LXR-α expression. Finally, overexpression of RBM38 rescues Angiotensin II-induced myocardial hypertrophy by regulating LXR-α dependent lipogenesis pathway. In conclusion, RBM38 Overexpression rescues Angiotensin II-induced myocardial hypertrophy by regulating LXR-α dependent lipogenesis pathway.
Subject(s)
Cardiomegaly/metabolism , Lipogenesis , Liver X Receptors/metabolism , Myocytes, Cardiac/metabolism , RNA-Binding Proteins/metabolism , Signal Transduction , Angiotensin II/adverse effects , Angiotensin II/pharmacology , Cardiomegaly/chemically induced , Cardiomegaly/genetics , Humans , Liver X Receptors/genetics , RNA-Binding Proteins/geneticsABSTRACT
Caduet, also known as amlodipine besylate and atorvastatin calcium (AM + AT) tablet, can improve cardiac and vascular remodeling in patients with spontaneous hypertension (SH), but the underlying mechanism remains unknown. The present study aimed to explore whether AM + AT improved hypertensive left ventricular and thoracic aortic remodeling by regulating connexin 43 (Cx43) phosphorylation. A total of 32 male spontaneous hypertension model rats (SHR) were randomly divided into four groups: SHR control group, amlodipine-alone group (SHR-AM), atorvastatin-alone (SHR-AT) and AM + AT group (SHR-AM + AT); 8 Wistar-Kyoto (WKY) rats with normal blood pressure were used as the normal control. Drugs were orally administered for 8 weeks; subsequently, body weight, heart rate (HR), left ventricular mass index (LVMI), blood pressure (BP), plasma lipid levels and morphological changes of myocardial tissue in each group were analyzed. The expression of total (T)-Cx43 and phosphorylated (P)-Cx43 protein in the left ventricular and thoracic aortic tissues was determined using western blotting and immunofluorescence double labeling. The results revealed that AM + AT significantly decreased LVMI and cardiomyocyte cross-sectional area compared with SHR-AM and SHR-AT group. The western blotting results demonstrated that AM + AT could inhibit the expression of T-Cx43 protein, but increased the expression of P-Cx43 in the left ventricular and thoracic aorta. Moreover, immunofluorescence results indicated AM + AT could also decrease the expression T-Cx43, and increase that of P-Cx43 in the left ventricular and thoracic aorta compared with AM and AT alone. Therefore, it was concluded that AM + AT may mitigate left ventricular and thoracic aorta remodeling in SH rats by enhancing Cx43 phosphorylation, and the efficacy of AM + AT was superior to that of AM and AT alone.
ABSTRACT
1. Endothelial dysfunction plays a critical role in the development and progression or pathogenesis of hypertension. Amlodipine, a calcium channel blocker, is an effective antihypertensive agent. We investigated the effects of amlodipine on endothelial dysfunction in mesenteric arteries from spontaneously hypertensive rats (SHR). 2. Eight-week-old SHR were treated with amlodipine (10 mg/kg per day) for 8 weeks. Control SHR and Wistar-Kyoto (WKY) rats were treated with saline. Systolic blood pressure (SBP) was measured by the tail-cuff method. Isometric tension changes of isolated mesenteric arterial rings were recorded continuously by a myograph system. Serum contents of malondialdehyde (MDA) and total nitrate/nitrite (NO(x) ) were determined. Vascular superoxide anion production was analysed with dihydroethidium (DHE) fluorescence. 3. The contractile responses to KCl and phenylephrine were greater in untreated SHR than in WKY. Acetylcholine (ACh)-induced relaxation was significantly impaired in untreated SHR. Amlodipine treatment reduced the contractions and improved relaxation to ACh. In WKY, relaxation to ACh was inhibited by N(G) -nitro-l-arginine methyl ester (l-NAME) and not changed by ascorbic acid. In untreated SHR, the response to ACh was unaffected by l-NAME, whereas it was improved by ascorbic acid. Amlodipine restored the inhibitory effect of l-NAME on ACh-induced relaxation, but ascorbic acid no longer exerted its facilitating effect. Amlodipine prevented the rise in SBP and ameliorated abnormalities in serum MDA and NO in untreated SHR. DHE assay showed an increased intravascular superoxide generation in untreated SHR, which was abrogated by amlodipine. 4. Treatment of SHR with amlodipine resulted in amelioration of endothelial dysfunction by anti-oxidant activity and improvement in NO availability.
