Protection from renal fibrosis, putative role of TRIB3 gene silencing.

BACKGROUND: Renal fibrosis is thought to be the common pathway in most cases of chronic kidney disease. Recently, TRIB3 was found to play an important role in progression of cardiac fibrosis in an insulin-resistant state. We investigated whether TRIB3 might participate in the pathogenesis of renal fibrosis in insulin-resistant rats. METHODS: We randomly separated 40 male Sprague-Dawley into 4 groups for treatment (n = 10 each): control and high-fat diet (HFD) with TRIB3 siRNA adenovirus transfection, vehicle transfection or HFD alone. Insulin resistance markers were measured. Renal tissues were stained with hematoxylin and eosin, Masson's trichrome and periodic acid-Schiff. RESULTS: Rats with HFD showed insulin resistance and TRIB3 overexpression. Upregulated TRIB3 expression could induce renal fibrosis accompanied by increased phosphorylation of extracellular signal-regulated kinase (ERK). Also, TRIB3 siRNA knockdown could ameliorate renal fibrosis, which was accompanied by decreased phosphorylation of ERK. CONCLUSIONS: TRIB3 gene silencing can attenuate renal fibrosis for beneficial effect on the development of renal fibrosis in chronic kidney disease in rat.

Overexpression of interleukin-18 aggravates cardiac fibrosis and diastolic dysfunction in fructose-fed rats.

Inflammation plays an important role in the pathophysiology of the metabolic syndrome (MS). We determined whether the overexpression of interleukin (IL)-18 could aggravate left ventricular (LV) remodeling and diastolic dysfunction in fructose-fed rats (FFRs). To create an animal model for MS, male Wistar rats received 10% fructose in water for 8 months. We used an adenovirus encoding rat IL-18 to overexpress IL-18 in FFRs by intravenous administration. IL-18 overexpression led to increases in collagen volume fraction and collagen deposition. LV systolic function was unaltered. But the LV end-diastolic pressure and the time constant of isovolumic relaxation (tau) were increased. Peak negative value of time derivative of LV pressure (-dp/dt) was decreased. Isovolumic relaxation time and myocardial index, as assessed by echocardiography, were increased. Overexpression of IL-18 leads to aggravated LV remodeling and dysfunction in FFRs. Attenuation of the inflammatory process may provide a novel therapeutic strategy in treating metabolic cardiomyopathy.

IL-18 overexpression promotes vascular inflammation and remodeling in a rat model of metabolic syndrome.

Although considerable evidence implicates the cytokine interlukin-18 (IL-18) in metabolic syndrome (MetS), the direct effect of IL-18 on vascular changes of MetS remains unknown. We investigated the chronic in vivo effect of IL-18 on development of MetS and vascular inflammation and remodeling by overexpressing IL-18 protein in fructose-fed rats (FFR), a model of MetS using intravenous administration of an adenovirus encoding rat IL-18. Increased serum IL-18 and vascular inflammatory response were found in FFR. Overexpression of IL-18 aggravated insulin resistance and enhance vascular inflammation and remodeling, which can be reflected by increased aortic expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and enhanced infiltration of macrophages and increased aortic wall thickness and wall-to-lumen ratio. Interestingly, the levels of interleukin-1 receptor-associated kinase 1 (IRAK1) and the activity of nucleus factor-kappaB (NF-kappaB) were also significantly increased. Together, these results indicated that chronic elevated IL-18 levels at a supraphsiological concentration aggravated insulin resistance, enhanced vascular inflammation and remodeling, probably by increasing the level of IRAK1 and the activity of NF-kappaB. Targeting expression of IL-18 or its specific downstream mediators may retard the progression of MetS and its complications.

Felodipine attenuates vascular inflammation in a fructose-induced rat model of metabolic syndrome via the inhibition of NF-kappaB activation.

AIM: Metabolic syndrome is associated with an increased incidence of atherosclerosis. Clinical studies have shown that calcium channel blockers (CCB) inhibit the progression of atherosclerosis. However, the underlying mechanism is unclear. We investigated the inhibitory effect of felodipine on adhesion molecular expression and macrophage infiltration in the aorta of high fructose-fed rats (FFR). METHODS: Male Wistar rats were given 10% fructose in drinking water. After 32 weeks of high fructose feeding, they were treated with felodipine (5 mg x kg(-1) x d(-1)) for 6 weeks. The control rats were given a normal diet and water. The aortic expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and the infiltration of macrophages were measured by real-time RT-PCR and/or immunohistochemistry. NF-kappaB activity was measured by electrophoretic mobility shift assay (EMSA). RESULTS: After 32 weeks of high fructose feeding, FFR displayed increased body weight, systolic blood pressure (SBP), serum insulin, and triglycerides when compared with the control rats. The aortic expressions of ICAM-1 and VCAM-1 were significantly increased in FFR than in the control rats and accompanied by the increased activity of NF-kappaB. FFR also showed significantly increased CD68- positive macrophages in the aortic wall. After treatment with felodipine, SBP, serum insulin, and the homeostasis model assessment decreased significantly. In addition to reducing ICAM-1 and VCAM-1, felodipine decreased macrophages in the aortic wall. EMSA revealed that felodipine inhibited NF-kappaB activation in FFR. CONCLUSION: Felodipine inhibited vessel wall inflammation. The inhibition of NF-kappaB may be involved in the modulation of vascular inflammatory response by CCB in metabolic syndrome.

Felodipine reduces cardiac expression of IL-18 and perivascular fibrosis in fructose-fed rats.

Metabolic syndrome is associated with accelerated macrovascular and microvascular coronary disease, cardiomyopathy, and elevated inflammatory status. To determine whether metabolic syndrome-associated elevation of the inflammatory cytokine interleukin-18 (IL-18) in serum and cardiac tissue, and its potential sequelae could be attenuated pharmacologically, we studied fructose-fed rats. The fructose-fed rats exhibited increases in systolic blood pressure (SBP), body weight, heart weight, left ventricular weight, and blood insulin. Serum IL-18 levels in these rats were also elevated significantly. These changes were significantly different compared to those in control rats. Perivascular fibrosis around coronary arterioles was evident in the fructose-fed rats, accompanied by a paralleled increase in IL-18 by immunohistochemical analysis and real time polymerase chain reaction. Felodipine attenuated the increased levels in serum IL-18 and cardiac IL-18 mRNA as well as coronary perivascular fibrosis. Thus, augmented IL-18 in serum and cardiac tissue in metabolic syndrome may contribute to the coronary perivascular fibrosis; felodipine administration can attenuate the inflammatory and fibrosis process.

Overexpression of TRB3 gene in adipose tissue of rats with high fructose-induced metabolic syndrome.

Insulin resistance is the physiopathologic foundation of metabolic syndrome. TRB3 has been revealed to be involved in insulin resistance in the liver by interacting directly with Akt and blocking its activation. Our investigation aims at exploring the relationship between metabolic syndrome and TRB3 mRNA expression in adipose tissue of rats. Two groups were studied as follows: the control group (CONTROL, n = 12) was fed a standard rodent chow, and the experimental group (Fructose n = 9) was fed a high-fructose diet. Body weight and systolic blood pressure were measured per 4 weeks. At the end of 38 weeks, levels of tribbles mRNAs in adipose tissue were determined by quantitative real-time polymerase chain reaction (PCR), and Akt/phospho-Akt expression was assessed by Western blot. Results show that levels of TRB1-3 mRNAs were expressed in adipose tissue of rats of both groups, and tribbles mRNAs were TRB1 (CONTROL: 0.00515, Fructose: 0.00497), TRB2 (CONTROL: 0.02104, Fructose: 0.01988), and TRB3 (CONTROL: 0.00457, Fructose: 0.00822), respectively. Of the three, TRB3 mRNA alone significantly increased by 94% in adipose tissue of fructose-fed rats compared with those in adipose tissue of the controls (P<0.05), and there was significant positive correlation between TRB3 mRNA levels and HOMA-R in fructose group (r = 0.68, P<0.05). Western blot analysis showed that phospho-Akt (Ser-473) expression was significantly decreased in adipose tissue of fructose-fed rats compared with controls (P<0.001). The present study suggests that TRB3 may be involved in metabolic syndrome by inhibiting activation of Akt in adipose tissue.

Impaired left ventricular systolic synchronicity in hypertensive patients with ventricular arrhythmias.

Left ventricular (LV) systolic synchronicity is impaired in hypertensive patients. Ventricular arrhythmias often co-exist in hypertensive patients; hypertension and ventricular arrhythmias have an adverse impact on cardiac function. However, the influence of ventricular arrhythmias on LV synchronicity was not clear. The objective of the present study was to investigate the influence of ventricular arrhythmias on LV synchronicity in hypertensive patients. Tissue Doppler imaging (TDI) was performed in 136 subjects. Group 1 consisted of 74 hypertensives without any arrhythmias; group 2 consisted of 30 hypertensive patients with ventricular arrhythmias; and the control group consisted of 32 normal subjects. Using three apical views, LV synchronicity was assessed by the maximal differences in time to peak myocardial systolic contraction (T(s)) and early diastolic relaxation (T(e)) between any two of the LV segments (T(s)-max, T(e)-max) and the standard deviation of T(s) (T(s)-SD) and T(e) (T(e)-SD) of all 12 segments. T(s)-max was significantly prolonged in group 2 compared with group 1 and the control group (93.70 +/- 20.97 ms vs. 79.48 +/- 25.46 ms [p<0.01] or 53.83 +/- 15.42 ms [p<0.001], respectively). T(s)-SD was also significantly prolonged in group 2 compared with group 1 and the control group (38.16 +/- 5.82 ms vs. 33.37 +/- 6.04 ms [p<0.05] or 24.01 +/- 3.58 ms [p<0.001], respectively). In conclusion, LV systolic synchronicity was impaired in hypertensive patients with ventricular arrhythmias, and TDI was shown to be useful for the detection of myocardial abnormalities in such patients.

[The effects of antidepressant treatment on efficacy of antihypertensive therapy in elderly hypertension].

OBJECTIVE: To explore the effect of antidepressant treatment on antihypertensive therapy of senile hypertension. METHODS: 138 cases of senile hypertension complicating with depression were studied. 103 senile hypertensive patients without depression in the same period served as controls. The patients were randomly divided into 3 groups as A, B and C for study. 12.5 mg/d hydrochlorothiazide and 30 mg/d release-controlling tablets of nifedipine were orally administrated as basic antihypertensive medication each group. Besides, 20 mg/d fluoxetine was additionally given to groups A and one tablet of almitrine l/d and 20 mg oryzanol 3/d were given to group B. The treatment lasted 12 weeks. RESULTS: In comparison with pre-treatment, the blood pressure at base line in sitting position and the average circadian SBP and DBP monitored with 24-hour ambulatory blood pressure monitoring (ABPM) was remarkably decreased in group A with statistical significance (P < 0.01). These blood pressure parameters in group B were also decreased as compared ith the pretreatment level brt with less statistical significance (P > 0.05). It was also noted tha with the addition of antidepressant fluoxetine, the manifestations of depression ere alleviated as shown by Hamilton depression (HAMD) scale. untoward reactions such as nausea, perspiration and skin rash were noted in a few patients, but none withdrew from the study. CONCLUSIONS: Antidepressant and antianxiety treatment is of benefit to the antihypertensive therapy in senile hypertensive patients with complications of depression and/or anxiety neurosis. Based on the results of this study, it is suggested that routine administration of antidepressants and antianxiety drugs should be carried out in senile hypertensive patients complicating with depression or anxiety.