Retinoid X receptor agonists alleviate fibroblast activation and post-infarction cardiac remodeling via inhibition of TGF-ß1/Smad pathway.

Retinoid X receptor (RXR), particularly RXRα, has been implicated in cardiovascular diseases. However, the functional role of RXR activation in myocardial infarction (MI) remains unclear. This study aimed to determine the effects of RXR agonists on MI and to dissect the underlying mechanisms. Sprague-Dawley (SD) rats were subjected to MI and then treated (once daily for 4 weeks) with either RXR agonist bexarotene (10 or 30 mg/kg body weight) or vehicle. Heart function was determined using echocardiography and cardiac hemodynamic measurements. Four weeks post MI, myocardial tissues were collected to evaluate cardiac remodeling. Primary cardiac fibroblasts (CFs) were treated with or without RXR ligand 9-cis-RA followed by stimulation with TGF-ß1. Immunoblot, immunofluorescence, and co-immunoprecipitation were performed to elucidate the regulatory role of RXR agonists in TGF-ß1/Smad signaling. In vivo treatment with Bexarotene moderately affects systemic inflammation and apoptosis and ameliorated left ventricular dysfunction after MI in rat model. In contrast, bexarotene significantly inhibited post-MI myocardial fibrosis. Immunoblot analysis of heart tissue homogenates from MI rats revealed that bexarotene regulated the activation of the TGF-ß1/Smad signaling pathway. In vitro, 9-cis-RA inhibited the TGF-ß1-induced proliferation and collagen production of CFs. Importantly, upon activation by 9-cis-RA, RXRα interacted with p-Smad2 in cytoplasm, inhibiting the TGF-ß1-induced nuclear translocation of p-Smad2, thereby negatively regulating TGF-ß1/Smad signaling and attenuating the fibrotic response of CFs. These findings suggest that RXR agonists ameliorate post-infarction myocardial fibrosis, maladaptive remodeling, and heart dysfunction via attenuation of fibrotic response in CFs through inhibition of the TGF-ß1/Smad pathway activation.

Blood pressure lowering effects of ß-blockers as add-on or combination therapy: A meta-analysis of randomized controlled trials.

The authors performed a meta-analysis to assess the efficacy of non-atenolol ß-blockers as add-on to monotherapy or as a component of combination antihypertensive therapy in patients with hypertension. The authors searched and identified relevant randomized controlled trials from PubMed until November 2021. Studies comparing blood pressure lowering effects of ß-blockers with diuretics, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs) were included. The analysis included 20 studies with 5544 participants. ß-blockers add-on to monotherapy significantly reduced systolic and diastolic blood pressure as compared with non-ß-blocker monotherapy (weighted mean difference in mm Hg [95% confidence interval]: -4.1 [-6.0, -2.2] and -3.7 [-4.6, -2.8], respectively). These results were consistent across the comparisons with diuretics (systolic pressure, -10.2 [-14.2, -6.2]; diastolic pressure, -5.4 [-8.2, -2.6]), CCBs (systolic pressure, -4.1 [-7.1, -1.0]; diastolic pressure, -2.8 [-4.1, -1.5]), and ACEIs/ARBs (systolic pressure, -2.9 [-4.3, -1.5]; diastolic pressure, -4.2 [-5.0, -3.4]). There was no significant difference in blood pressure lowering effects between combinations with and without a ß-blocker (systolic pressure, -1.3 mm Hg [-5.8, 3.2]; diastolic pressure, -.3 mm Hg [-2.7, 2.1]). Metoprolol add-on or combination therapy had a significantly greater blood pressure reduction than non-ß-blocker therapy (systolic pressure, -3.6 mm Hg [-5.9, -1.3]; diastolic pressure, -2.1 mm Hg [-3.5, -.7]). In conclusion, non-atenolol ß-blockers are effective in lowering blood pressure as add-on to monotherapy or as a component of combination antihypertensive therapy. In line with the current hypertension guideline recommendations, ß-blockers can and should be used in combination with other antihypertensive drugs.

2019 Chinese Hypertension League guidelines on home blood pressure monitoring.

In China, automated blood pressure monitors have been readily available for home use. Home blood pressure monitoring has been indispensable in the management of hypertension. There is therefore a need to establish guidelines for home blood pressure monitoring on the basis of the 2012 consensus document. In this guidelines document, the committee put forward recommendations on the selection and calibration of blood pressure measuring devices, the frequency (times) and duration (days) of blood pressure measurement, and the diagnostic threshold of home blood pressure.

Early treatment with losartan effectively ameliorates hypertension and improves vascular remodeling and function in a prehypertensive rat model.

AIMS: Pharmacological treatment of prehypertension may ameliorate hypertension and improve vascular structure and function. This study investigated 1) whether early treatment with either losartan or amlodipine at the onset of prehypertension can prevent hypertension and 2) whether losartan and amlodipine equally improve vascular remodeling and function in a rat model of hypertension. MATERIALS AND METHODS: Stroke-prone spontaneously hypertensive (SHRSP) rats were administered losartan, amlodipine or saline for 6 or 16weeks at the onset of prehypertension. Wistar-Kyoto rats were used as a control. All groups were observed for 40weeks. Systolic blood pressure was measured using the tail-cuff method. Vascular structure and function were determined by microscopy and vascular ring contractility assays, respectively. Angiotensin II (Ang II) and aldosterone (Aldo) were measured by radioimmunoassays. Angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) expression was measured by western blot. KEY FINDINGS: Losartan effectively reduced progression from prehypertension to hypertension as well as vascular remodeling and improved vascular contractility in SHRSP rats. Long-term losartan (16weeks) had greater benefits than short-term (6weeks) treatment. Losartan increased Ang II and decreased Aldo levels in the serum and vessel walls of resistance vessels in a time-dependent manner. Losartan significantly decreased AT1R and increased AT2R vascular expression. Amlodipine had no effect on vascular AT1R and AT2R expression. SIGNIFICANCE: Losartan administered at the onset of prehypertension is more effective than amlodipine in ameliorating hypertension and improving vascular remodeling and function, which is likely mediated by the renin-angiotensin-aldosterone system.

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.

Effects of Losartan and Amlodipine on Left Ventricular Remodeling and Function in Young Stroke-Prone Spontaneously Hypertensive Rats.

BACKGROUND: The purpose of this study was to evaluate the effects of prehypertensive losartan and amlodipine administration on left ventricular (LV) remodeling and function in spontaneously hypertensive rats-stroke prone (SHRSP). METHODS: Spontaneously hypertensive rats-stroke prone were prehypertensively administered losartan, amlodipine, or vehicle. Wistar-Kyoto rats were used as a control. Blood pressure of the rats was determined by tail-cuff method, and LV structure and function were measured by echocardiography and LV cannulation. Collagen volume fraction was analyzed by picrosirius red staining. Protein expressions of brain natriuretic peptide (BNP) and angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors were determined by use of the Western blotting method. RESULTS: Although both drugs downregulated BNP protein expression, the LV remodeling and function were more improved with losartan than with amlodipine treatment. Losartan upregulated AT1R and downregulated AT2R protein expression. CONCLUSIONS: Both drugs inhibited LV remodeling and improved LV function in prehypertensively treated SHRSP. Losartan provided better continued heart protection, potentially due to its persistent inhibition of AT1R and activation of AT2R in the myocardium. KEY WORDS: Amlodipine; Blood pressure; Heart; Losartan; Prehypertension.

Differential effects of antihypertensive treatments on apoptosis, oxidative stress, and expression of angiotensin receptors in the cerebral cortex from the onset of prehypertension and hypertension in stroke-prone spontaneous hypertensive rats.

To investigate the effects of losartan and amlodipine on cell apoptosis in the cerebral cortex of stroke-prone spontaneously hypertensive rats (SHRSP) from the onset of prehypertension or hypertension. SHRSP were randomly divided into five experimental groups that were administered losartan, amlodipine (n=8 in each group; 4 weeks old or 10 weeks old), or vehicle, respectively. Wistar-Kyoto rats were used as control animals. Systolic blood pressure was measured using the tail-cuff method every 2 weeks. At 20 weeks of age, apoptosis was analyzed by TdT-mediated dUTP-biotin nick end labeling, and the level of angiotensin II was measured by radioimmunoassay. Protein expressions of gp91(phox), superoxide dismutase, and angiotensin II type 1 (AT1R) and type 2 (AT2R) receptors in the cerebral cortex were detected by western blot. Losartan and amlodipine effectively delayed the progression of systolic blood pressure elevation, especially from the onset of prehypertension, and they had no obvious effects on the level of angiotensin II. In addition, treatment with losartan or amlodipine significantly decreased cell apoptosis, downregulated the protein expression of gp91(phox), and upregulated the protein expression of superoxide dismutase. The protein expressions of AT1R and AT2R were decreased by the administration of both drugs. No difference was found in the expression of AT1R among the drug treatment groups, whereas the expression of AT2R was increased in rats with increased blood pressure. Amlodipine, especially from the onset of prehypertension, was more effective than losartan in reducing apoptosis in the cerebral cortex in SHRSP. This may be related to the antioxidative stress properties of amlodipine.

Metformin reduces vascular endothelial dysfunction caused by an acute glucose load in patients with hypertension.

BACKGROUND: To investigate the effects of a single dose of metformin (MF) on endothelium-dependent vasodilatation and serum antioxidant and free fatty acid levels in patients with primary hypertension (PH) after an acute glucose load. MATERIALS AND METHODS: Patients with untreated PH were randomized to a no-metformin group (PH, n = 34) and a metformin group (PH+ MF, n = 28) who received a single dose of 500 mg metformin before testing. Healthy volunteers (n = 31) served as a control group. Brachial artery endothelium-dependent flow-mediated vasodilatation (FMD) was determined at 0, 1, 2 and 3 h after glucose load. Levels of serum superoxide dismutase (SOD), total antioxidant capacity (T-AOC), anti-superoxide anion free radical (AntiO2) and free fatty acids (FFA) were measured. RESULTS: The FMD in the PH group decreased significantly 1 h after glucose load (PH: 10.9 ± 2.9% vs 13.67 ± 3.42% before glucose load). Metformin inhibited the effects of glucose load on FMD. At 1 h after acute glucose load, the concentrations of SOD, T-AOC and AntiO2 in the PH group decreased significantly compared with their fasting levels, and metformin inhibited the acute glucose load-induced decline in SOD and T-AOC levels. CONCLUSIONS: Metformin can prevent transient endothelial dysfunction caused by acute glucose load in patients with PH.

Effects of combined glucose and fat load on endothelium-dependent brachial artery vasodilatation in hypertensive patients.

INTRODUCTION: This study investigated the effects of combined glucose and fat load on glucose and lipid metabolism, as well as on vascular endothelial function, in hypertensive patients. METHODS AND RESULTS: A total of 98 hypertensive patients were randomly divided into 3 groups that received an oral fat tolerance test (OFTT), an oral glucose tolerance test (OGTT) or a combined oral glucose and fat tolerance test (OGFTT). Endothelium-dependent flow-mediated brachial artery dilation (FMD) was measured by vascular ultrasound and was used as an indicator of vascular endothelial function. There were no significant differences in demographics or clinical characteristics among the 3 groups before the study. Immediately after the OGFTT, the serum triglyceride levels and the area under the curve for serum glucose in the OGFTT group were not significantly different from those in the other 2 groups. However, the 1-hour FMD in the OGFTT group was significantly reduced compared with that of the OGTT group (5.45 ± 0.75 versus 9.46 ± 1.32, P < 0.05), and the 4-hour FMD in the OGFTT group was also significantly reduced compared with the OFTT group (8.56 ± 1.09 versus 9.76 ± 2.00, P < 0.05). CONCLUSION: A combined glucose and fat load has a cumulative effect on vascular endothelial dysfunction in hypertensive patients.

[Impact of obesity and hypertension on left atrium size].

OBJECTIVE: To investigate the impact of obesity and hypertension on the size of the left atrium. METHODS: A total of 383 subjects were divided into normal group (NS, n = 95), hypertension group (HT, n = 97), obesity group (OB, n = 98) and hypertension with obesity group (HT + OB, n = 93). Clinical information, echocardiographic parameters and left atrial size in the four groups were compared. RESULTS: (1) The left atrial volume index (LAVI) was arranged in the order: HT + OB > OB > HT > NS (28.07 ± 6.63 > 24.61 ± 4.89 > 22.73 ± 5.16 > 19.18 ± 4.82 ml/m, P < 0.05); Difference on LAVI was significant in four groups after adjusting for age, gender, HR, FPG, TC, TG and HDL (P < 0.05). (2) Pearson correlation analysis showed closer correlation between BMI with LAVI compared to SBP and DBP with LAVI (r values: 0.505, 0.240, 0.209, P < 0.001). After adjusting for other factors, the correlation between BMI and LAVI remains significant (ß = 0.411, P < 0.001) while no significant relationship between SBP, DBP and LAVI was found. One unit BMI increase is associated with 0.052 cm enlargement of left atrial diameter (LAD), 1.053 ml increase of left atrial volume (LAV) and 0.710 ml/m increase of LAVI. CONCLUSION: The impact of obesity on the size of left atrium is greater than that of hypertension. Obesity and hypertension have synergistic effects on enlarging left atria.

[Association between metabolic syndrome and incidence of atrial fibrillation in essential hypertensive patients without left ventricular hypertrophy].

OBJECTIVE: To investigate the association between metabolic syndrome (MS) and the incidence of atrial fibrillation (AF) in essential hypertensive (EH) patients without left ventricular hypertrophy. METHODS: A total of 972 EH without left ventricular hypertrophy were divided into EH + non MS group (n = 606) and EH + MS group (n = 366). Incidence of AF were compared between two groups. RESULTS: (1) Incidence of AF in EH + MS group was significantly higher than that in EH + non MS group (12.84% vs. 6.93%, P < 0.01). (2) Left atrial diameter (LAD), left ventricular end-diastolic diameter (LVEDd), interventricular septum thickness (IVS), left ventricular posterior wall thickness (LVPW) and left ventricular mass (LVM) were all significantly higher in EH + MS group than those in EH + non MS group (all P < 0.01) while left ventricular mass index (LVMI) and ejection fraction (EF) were similar between two groups. (3) Logistic regression analysis showed age, hypertension duration, LAD, LVEDd and MS were significantly correlated with incidence of AF in EH patients (OR: 1.683, 1.308, 2.262, 3.848 and 1.853, P < 0.05) and obesity was the independent predictor for incidence of AF (OR: 1.706, P = 0.029). CONCLUSION: MS was associated with increased incidence of AF in EH patients without left ventricular hypertrophy in this cohort.

[Impact of acute glucose and fat loading on endothelium dependent vasodilation in patients with essential hypertension].

OBJECTIVE: To explore the influence of acute glucose and fat loading on endothelium dependent flow-mediated vasodilation (FMD) in patients with essential hypertension (EH). METHODS: Patients with EH were randomly divided into three groups: oral glucose loading alone (n = 26), oral standardized fat loading alone (n = 38), combined glucose and fat loading (n = 34). FMD of the brachial artery was assessed by high resolution ultrasound technique respectively. RESULTS: (1) Compared to control group, postprandial abnormal serum triglyceride metabolism was evidenced and FMD was significantly reduced and the lowest FMD occurred at 4 hours and returned to the baseline level at 8 hours post fat loading alone in EH patients. (2) GS-AUC and 1 hour glucose were significantly higher in EH patients than in controls (all P < 0.05), FMD was also significant decreased (-31.4%) at 1 hour and returned to baseline level at 2 hours post oral glucose loading. (3) After combined glucose and fat loading, FMD at 1 hour (5.45 ± 1.93 vs. 9.46 ± 3.33, P < 0.05) was significantly lower than that in glucose loading alone and FMD at 4 hours (7.98 ± 1.64 vs. 9.66 ± 2.26, P < 0.05), was also lower than that in fat loading alone in EH patients. (4) FMD was negatively correlated with SBP, GS-AUC, DBP, TG-AUC (γ = -0.46, -0.44, -0.41, -0.38, respectively, all P < 0.05). CONCLUSION: Combined glucose and fat loading additively reduced FMD in hypertensive patients.

[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.