Retinoid X receptor agonists inhibit hypertension-induced myocardial hypertrophy by modulating LKB1/AMPK/p70S6K signaling pathway.

BACKGROUND: Retinoid X receptor (RXR) has been demonstrated to play an important role in cardiac development and has been implicated in cardiovascular diseases. This study aimed to examine the effects of RXRα agonist bexarotene on pathological left ventricular hypertrophy (LVH) in a spontaneously hypertensive rat (SHR) model and the underlying mechanism. METHODS: WKY rats served as controls. SHRs were randomized into 3 groups at the age of 4 weeks and were treated (once daily for 12 weeks) with either bexarotene (30 or 100mg/kg body weight) or vehicle alone. Echocardiography was performed to determine cardiac structure and function. Neonatal cardiomyocytes were treated with AngII (10(-7) mmol/L) with or without the indicated concentration of RXRα ligand 9-cis-RA. The protein abundances of ß-actin, RXRα, LKB1, phospho-LKB1, AMPK, phospho-AMPK, P70S6K, phospho-P70S6K, ACE, and AT1 receptor were measured along with blood pressure, body weight and angiotensin II (Ang II) levels. The effects of LKB1 downregulation by LKB1 small, interfering RNA were examined. RESULTS: Treatment of SHRs with bexarotene resulted in significant inhibition of LVH without eliminating hypertension. Immunoblot with heart tissue homogenates from SHRs revealed that bexarotene activated the LKB1/AMPK signaling pathway and inhibited p70S6K. However, the increased Ang II levels in SHR serum and heart tissue were not reduced by bexarotene treatment. Treatment of cardiomyocytes with Ang II resulted in significantly reduced LKB1/AMPK activity and increased p70S6K activity. 9-cis-RA antagonized Ang II-induced LKB1/AMPK and p70S6K activation changes in vitro. CONCLUSIONS: RXR agonists prevent the inhibition of the LKB1/AMPK/p70S6K pathway and regulate protein synthesis to reduce LVH. This antihypertrophic effect of bexarotene is independent of blood pressure.

Long-term prehypertension treatment with losartan effectively prevents brain damage and stroke in stroke-prone spontaneously hypertensive rats.

Prehypertension has been associated with adverse cerebrovascular events and brain damage. The aims of this study were to investigate ⅰ) whether short­ and long-term treatments with losartan or amlodipine for prehypertension were able to prevent blood pressure (BP)-linked brain damage, and ⅱ) whether there is a difference in the effectiveness of treatment with losartan and amlodipine in protecting BP-linked brain damage. In the present study, prehypertensive treatment with losartan and amlodipine (6 and 16 weeks treatment with each drug) was performed on 4-week­old stroke-prone spontaneously hypertensive rats (SHRSP). The results showed that long-term (16 weeks) treatment with losartan is the most effective in lowering systolic blood pressure in the long term (up to 40 weeks follow-up). Additionally, compared with the amlodipine treatment groups, the short­ and long-term losartan treatments protected SHRSP from stroke and improved their brains structurally and functionally more effectively, with the long-term treatment having more benefits. Mechanistically, the short­ and long-term treatments with losartan reduced the activity of the local renin-angiotensin-aldosterone system (RAAS) in a time-dependent manner and more effectively than their respective counterpart amlodipine treatment group mainly by decreasing AT1R levels and increasing AT2R levels in the cerebral cortex. By contrast, the amlodipine treatment groups inhibited brain cell apoptosis more effectively as compared with the losartan treatment groups mainly through the suppression of local oxidative stress. Taken together, the results suggest that long-term losartan treatment for prehypertension effectively protects SHRSP from stroke-induced brain damage, and this protection is associated with reduced local RAAS activity than with brain cell apoptosis. Thus, the AT1R receptor blocker losartan is a good candidate drug that may be used in the clinic for long-term treatment on prehypertensive populations in order to prevent BP-linked brain damage.

[Endothelial dysfunction and target organ damage in hypertensive patients complicating with or without metabolic syndrome].

OBJECTIVE: To investigate the impacts of metabolic syndrome (MS) on endothelial function and target organ damage in hypertensive patients. METHODS: Patients with essential hypertension (EH) were divided into two groups: hypertension and metabolic syndrome (EH + MS, n = 61), hypertension without metabolic syndrome (EH + nonMS, n = 95) and 31 healthy subjects served as normal control (NC). The change of brachial artery vascular diameter, blood flow volume and vascular resistance after reactive hyperemia were measured by color Doppler ultrasonography. RESULTS: (1) Triglyceride (TG), fasting blood glucose (FBG), body mass index (BMI) were higher in EH + MS group than that in EH + nonMS group (P < 0.05). (2) Endothelium-dependent Dilatation (FMD%) and rate of flow volume of reactive hyperemia were significantly lower in EH + MS group than that in EH + nonMS and NC group [(7.08 +/- 3.21)% vs. (8.18 +/- 1.74)% and (10.41 +/- 4.52)%, P < 0.05 and 0.01 respectively; (154.19 +/- 78.94)% vs. (196.44 +/- 64.22)% and (221.81 +/- 89.64)%, P < 0.05 and 0.01 respectively], while these parameters were similar between EH + nonMS and NC groups (P > 0.05). (3) The high sequence of forearm dilatation capability was also significantly reduced in EH + MS group compared to other groups. (4) The incidences of carotid atherosclerotic plaque and left ventricular hypertrophy (LVH) were significantly increased in EH + MS group compared to EH + nonMS group and NC group. (5) FMD was correlated with age, gender, smoking, SBP, DBP, TG, Fib respectively (P < 0.05). Intima-media thickness (IMT) of carotid artery was positively related with age, smoking, SBP, DBP, BMI, TG, Fib respectively. The left ventricular mass index (LVMI) was positively related with age, smoking, SBP, DBP, BMI, TG respectively. FMD was negatively related with IMT and LVMI respectively (P < 0.01). CONCLUSION: Metabolic syndrome further aggravated endothelial dysfunction and target organ damage in patients with essential hypertension.