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Introduction Angiotensin (Ang) II, the main effector of the renin-angiotensin system (RAS), has recently shown to enhance the expression of Profilin-1, which functions as a crucial regulator in actin polymerisation and cytoskeleton remodelling by activation of the hypertrophic signalling cascades such as mitogen-activated protein kinase (MAPK) signalling, contributing to myocardial hypertrophy and ventricular re-modelling. The key peptidase action of angiotensin-converting enzyme 2 (ACE2) is degradation of Ang II to Ang (1–7), functioning effectively as a negative regulator of the RAS. We hypothesised that loss of ACE2 accelerates myocardial hypertrophy and ventricular dysfunction by suppressing Ang II-mediated activation of MAPK signalling and Profilin-1 expression in heart. Methods & Results Ten-week old male ACE2 knockout (ACE2KO, Ace2 −/y ) and their littermate wildtype (WT, Ace2 +/y ) mice were used. An osmotic minipump (model 1002; USA) was implanted subcutaneously at the dorsum of the neck to infuse a pressor dose of Ang II (1.5 mg/kg/day) or saline (Vehicle) for 14 days. We characterised the functional, structural and molecular changes in the heart in response to pressure overload by echocardiography, TaqMan real-time PCR, and Western blot analysis. Compared with WT mice, loss of ACE2 resulted in worsening myocardial hypertrophy and pathological remodelling in ACE2 KO mice in response to Ang II, associated with increased expression of Profilin-1 and enhanced levels of hypertrophy markers (atrial natriuretic factor and brain natriuretic peptide). These changes were linked with greater activation of protein kinase Ca (PKCa) protein and phosphorylation of the extracellular signal-regulated protein kinase (ERK1/2), Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3), but not p38-mitogen-activated protein kinase (MAPK) signalling in Ang II-infused ACE2 KO mice. Conclusions Loss of ACE2 augments Ang II-induced myocardial hypertrophy and adverse remodelling by the enhanced Profilin-1 expression. These changes have been associated with activation of PKC signalling, the MAPK and JAK2/STAT3 phosphorylation pathways, suggesting a critical role of ACE2 in the suppression of Ang II-mediated myocardial hypertrophy, ventricular remodelling and heart failure. Drugs that influence the expression and activity of ACE2 may be potential avenues in the prevention and treatment of heart diseases. This work was supported by National Natural Science Foundation of China (Grant 30973522 & 30700328), and the Canadian Institute for Health Research (GYO, 86602 & 84279).

Objective To evaluate the efficacy and safety of olmesartan (OLM) and olmesartan plus hydrochlorothiazide (fixed-dose combination of OLM/HCTZ 20 mg/12.5 mg) combined with amlodipine (AML) in Chinese patients with mild to moderate essential hypertension who had insufficient response for AML mono-therapy. Methods This was an open label, non-comparative, multicenter clinical trial. The patients who had not achieved targeted BP (defined as DBP 20 mmHg. Results In the intent-to-treat analysis (n = 409), the rate of the responders at the end of week 4, 8, 12, 16 was 76.3%, 86.3%, 95.4%, 97.1%, respectively. In terms of DM subjects (n = 54), the rate was 88.9% at the end of treatment. The mean changes of blood pressure from baseline in all subjects at week 4, 8, 12 and 16 were as below. Only one SAE (no drug related) was reported during the study period. Conclusions In Chinese hypertensive patients with insufficient response for AML mono-therapy, OLM and OLM plus HCTZ combined with AML are efficacious in lowering BP and have an acceptable safety and tolerability profile.

Objectives To compare the prevalence of hemodynamically significant stenosis between renal arteries with and without variations in resistant hypertensive patients, and to determine whether aberrant renal arteries are associated with higher renin activity and impaired renal function in essential hypertensive patients. Methods 292 consecutive resistant hypertensives (212 male and 80 female, mean age 47.4 ± 15.7 yrs) underwent renal artery CTA or MRA to screen for secondary hypertension, two blinded readers evaluated CTA and MRA images for the presence of aberrant renal arteries and hemodynamically significant renal artery stenosis ( > 50%), and discrepancies were resolved by consensus reading. For all the patients, blood samples were collected in the morning after been out of bed for at least 2 h to assess plasma renin activity and aldosterone level, GFR was measured by 99mTc-DTPA to assess bilateral renal function. Results A single renal artery was present in both kidneys in 76.4% of the patients. Renal artery variations were found in 23.6% of the cases, including multiple renal arteries in 0.7%, accessory renal arteries in 21.9%, and early division in 2.0%. There was no difference in the prevalence of significant renal artery stenosis between patients with and without aberrant renal arteries (23.3% vs, 22.4%, P = 0.87). For patients with aberrant renal arteries, there was no difference in the prevalence of renal artery stenosis between renal arteries with and without variations (13.0% vs, 11.6%, P = 0.71). Among the patients diagnosed with essential hypertension, 53/226(23.5%) were with renal artery variations, 173/226 (76.5%) were not. Aldosterone level (log-transformed) was similar between these two groups (219.4 ± 116.5 pg/ml vs. 211.1 ± 153.6 pg/ml, P = 0.58). However, plasma renin activity was slightly higher in the former group (3.52 ± 2.42 ng/ml·h vs. 3.19 ± 2.74 ng/ml·h, P = 0.02). Self-paired t-test revealed that there was no difference in GFR between kidneys supplied by renal arteries with and without variations (46.9 ± 10.8 vs. 45.0 ± 11.8, P = 0.29). Conclusions Renal artery variations are not associated with higher susceptibility to developing renal artery stenosing lesions and impaired renal function. Essential hypertensives with aberrant renal arteries are prone to have high plasma renin activity.

Objectives This study aims to investigate different patterns of aortic stiffness and vasodilation in spontaneously hypertensive rats treated with β-blockers, with or without vasodilatory properties. Methods Spontaneously hypertensive rats (SHRs) were treated with metoprolol (200 mg kg −1 d −1 ), arotinolol (30 mg kg −1 d −1 ), and nebivolol (15 mg kg −1 d −1 ) for 8 weeks. Age-matched Wistar-Kyoto rats and untreated SHRs were used as controls. Central arterial pressure and pulse wave velocity were evaluated via catheter pressure transducers. The rings of rat aorta, and renal and mesenteric arteries were evaluated by isometric force recording. Collagen was assessed by immunohistochemistry, while endothelial nitric oxide synthase (eNOS) and eNOS phosphorylation (p-eNOS) were analysed by western blotting. Nitric oxide and reactive oxygen species were measured in human aortic endothelial cells by using fluorescent probes. Results Data showed that nebivolol and arotinolol, rather than metoprolol, markedly decreased central arterial pressure and pulse wave velocity at week 8, and compared to metoprolol, both nebivolol and arotinolol obviously increased vasorelaxation, aortic vasorelaxation to acetylcholine and p-eNOS/eNOS, and the effects of nebivolol were more pronounced. Besides, aortic collagen depositions in the nebivolol and arotinolol groups were reduced compared with those in the metoprolol group or untreated SHRs. Nebivolol and arotinolol produced more nitric oxide and had higher oxygen radical-scavenging capacities compared to metoprolol in the endothelial cells. Intriguingly, a potassium channel inhibitor (4-aminopyridine) caused a significant reduction in artinolol-induced vasorelaxation, but not nebivolol. Conclusions These findings suggested that vasodilating β-blockers with nitric oxide production may cause increased reduction of arterial stiffness via different mechanisms.