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Concept: Angiotensin receptor

170

BACKGROUND: Laminin-alpha2-deficient congenital muscular dystrophy (MDC1A) is a severe muscle-wasting disease for which no curative treatment is available. Antagonists of the angiotensin II receptor type 1 (AT1), including the anti-hypertensive drug losartan, have been shown to block also the profibrotic action of transforming growth factor (TGF)-beta and thereby ameliorate disease progression in mouse models of Marfan syndrome. Because fibrosis and failure of muscle regeneration are the main reasons for the severe disease course of MDC1A, we tested whether L-158809, an analog derivative of losartan, could ameliorate the dystrophy in dyW/dyW mice, the best-characterized model of MDC1A. METHODS: L-158809 was given in food to dyW/dyW mice at the age of 3 weeks, and the mice were analyzed at the age of 6 to 7 weeks. We examined the effect of L-158809 on muscle histology and on muscle regeneration after injury as well as the locomotor activity and muscle strength of the mice. RESULTS: We found that TGF-beta signaling in the muscles of the dyW/dyW mice was strongly increased, and that L-158809 treatment suppressed this signaling. Consequently, L-158809 reduced fibrosis and inflammation in skeletal muscle of dyW/dyW mice, and largely restored muscle regeneration after toxin-induced injury. Mice showed improvement in their locomotor activity and grip strength, and their body weight was significantly increased. CONCLUSION: These data provide evidence that AT1 antagonists ameliorate several hallmarks of MDC1A in dyW/dyW mice, the best-characterized mouse model for this disease. Because AT1 antagonists are well tolerated in humans and widely used in clinical practice, these results suggest that losartan may offer a potential future treatment of patients with MDC1A.

Concepts: Muscle, Muscular system, Angiotensin, Angiotensin II receptor antagonist, Mice, Muscle spindle, Angiotensin receptor, Angiotensin II receptor type 2

170

Chronic treatment with angiotensin receptor blockers is largely accepted for protecting cerebral circulation during hypertension, but beneficial effects of short-term treatments are questionable, as highlighted by the recent SCAST trial. We compared the impact of 10 days treatment with candesartan (as SCAST) versus telmisartan (previously described to reverse arteriolar remodeling, chronic treatment) on pial arterioles of spontaneously hypertensive rats (SHR). We explored whether PPAR-gamma agonist activity or AT(1) receptor blockade are involved in their differential effects. In the first study, 4-month-old male SHR were treated with telmisartan (TELMI, 2 mg/kg per day) or candesartan cilexetil (CANDE, 10 mg/kg per day) and compared to vehicle treated SHR and normotensive WKY. In a second study, SHR were treated with CANDE, pioglitazone (a PPAR-gamma agonist, PIO 2.5 mg/kg per day) or CANDE+PIO, compared to TELMI. Internal diameter of pial arterioles (ID, cranial window) was measured at baseline, during hemorrhage-induced hypotension, or following suffusion of Ang II (10(-6) mol/L) or EDTA inactivation of smooth muscle cells (passive ID). PPAR-gamma and eNOS (target gene of PPAR-gamma) mRNA were evaluated in brain microvessels. For similar antihypertensive effects, TELMI (+44% versus SHR), but not CANDE, increased baseline ID. During hemorrhage, ID in TELMI group was similar to WKY, while ID in SHR and CANDE remained lower. In the second study, TELMI (+36%, versus SHR) and CANDE+PIO (+43%) increased baseline ID, but not CANDE or PIO alone. TELMI (-66%) and CANDE+PIO (-69%), but neither CANDE nor PIO alone, decreased Ang II-induced vasoconstriction. CANDE+PIO, but not CANDE, increased passive ID. In both studies, PPAR-gamma and eNOS expressions were higher in TELMI than CANDE. Short-term treatment with TELMI, but not with CANDE, reverses narrowing of pial arteriolar ID in SHR. This may involve PPAR-gamma related mechanisms, since CANDE+PIO treatment induced similar effects, and a better blockade of AT(1) receptors.

Concepts: Hypertension, Blood pressure, Smooth muscle, Angiotensin, Angiotensin II receptor antagonist, Angiotensin receptor, Candesartan, Angiotensin II receptor antagonists

168

The aim of the present study was to evaluate the cardiovascular effects of the novel bradykinin B1 receptor antagonist BI-113823 following myocardial infarction (MI) and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin II type 1 (AT1) receptor antagonist after MI in rats.

Concepts: Myocardial infarction, Receptor, Angiotensin, Angiotensin II receptor antagonist, G protein coupled receptors, Angiotensin receptor, Bradykinin receptor B1, Angiotensin II receptor type 1

164

Angiotensin-(1-7) [Ang-(1-7)] is a biologically active heptapeptide that may counterbalance the physiological actions of angiotensin II (Ang II) within the renin-angiotensin system (RAS). Here, we evaluated whether activation of the Mas receptor with the oral agonist, AVE 0991, would have renoprotective effects in a model of adriamycin (ADR)-induced nephropathy. We also evaluated whether the Mas receptor contributed for the protective effects of treatment with AT1 receptor blockers. ADR (10 mg/kg) induced significant renal injury and dysfunction that was maximal at day 14 after injection. Treatment with the Mas receptor agonist AVE 0991 improved renal function parameters, reduced urinary protein loss and attenuated histological changes. Renoprotection was associated with reduction in urinary levels of TGF-β. Similar renoprotection was observed after treatment with the AT1 receptor antagonist, Losartan. AT1 and Mas receptor mRNA levels dropped after ADR administration and treatment with losartan reestablished the expression of Mas receptor and increased the expression of ACE2. ADR-induced nephropathy was similar in wild type (Mas(+/+) ) and Mas knockout (Mas (-/-)) mice, suggesting there was no endogenous role for Mas receptor activation. However, treatment with Losartan was able to reduce renal injury only in Mas(+/+) , but not in Mas (-/-) mice. Therefore, these findings suggest that exogenous activation of the Mas receptor protects from ADR-induced nephropathy and contributes to the beneficial effects of AT1 receptor blockade. Medications which target specifically the ACE2/Ang-(1-7)/Mas axis may offer new therapeutic opportunities to treat human nephropathies.

Concepts: Physiology, Receptor antagonist, Agonist, Angiotensin, Renin-angiotensin system, Inverse agonist, Receptor theory, Angiotensin receptor

153

Angiotensin II receptor blockers (ARBs) is a well-tolerated class of antihypertensive agents, exhibiting effective antihypertensive and cardiovascular protective function. The objective of the study was to examine the efficacy and safety of Allisartan Isoproxil, a newly developed, selective, nonpeptide blocker of the angiotensin II type 1 receptor (AT1R), in essential hypertensive patients at low-medium risk.

Concepts: Clinical trial, Blood pressure, Angiotensin, Renin-angiotensin system, Angiotensin II receptor antagonist, Angiotensin receptor, Angiotensin II receptor type 2, Beta blocker

38

Activation of the brain renin-angiotensin system (RAS) stimulates energy expenditure through increasing of the resting metabolic rate (RMR), and this effect requires simultaneous suppression of the circulating and/or adipose RAS. To identify the mechanism by which the peripheral RAS opposes RMR control by the brain RAS, we examined mice with transgenic activation of the brain RAS (sRA mice). sRA mice exhibit increased RMR through increased energy flux in the inguinal adipose tissue, and this effect is attenuated by angiotensin II type 2 receptor (AT2) activation. AT2 activation in inguinal adipocytes opposes norepinephrine-induced uncoupling protein-1 (UCP1) production and aspects of cellular respiration, but not lipolysis. AT2 activation also opposes inguinal adipocyte function and differentiation responses to epidermal growth factor (EGF). These results highlight a major, multifaceted role for AT2 within inguinal adipocytes in the control of RMR. The AT2 receptor may therefore contribute to body fat distribution and adipose depot-specific effects upon cardio-metabolic health.

Concepts: Metabolism, Epidermal growth factor, Fat, Adipose tissue, Angiotensin, Adipocyte, Angiotensin receptor, Resistin

28

Angiotensin II type 1 receptor (AT1R) mediates the cardiovascular actions of angiotensin II. Growing studies have revealed the underlying association between AT1R-A1166C (rs5186) polymorphism and coronary heart disease (CHD) among the East Asia population.

Concepts: Heart, Heart disease, Cardiovascular system, Angiotensin, Angiotensin II receptor antagonist, Asia, East Asia, Angiotensin receptor

27

Preeclampsia is a life-threatening pregnancy disorder that is widely thought to be triggered by impaired placental development. However, the placenta-related pathogenic factors are not fully identified, and their underlying mechanisms in disease development remain unclear. Here, we report that the protein level and enzyme activity of tissue transglutaminase (TG2 or tTG), the most ubiquitous member of a family of enzymes that conducts post-translational modification of proteins by forming ε-(γ-glutamyl)-lysine isopeptide bonds, are significantly elevated in placentas of preeclamptic women. TG2 is localized in the placental syncytiotrophoblasts of patients with preeclampsia where it catalyzes the isopeptide modification of the angiotensin receptor type 1 (AT1). To determine the role of elevated TG2 in preeclampsia, we used a mouse model of preeclampsia based on injection of AT1-agonistic autoantibody. A pathogenic role for TG2 in preeclampsia is suggested by in vivo experiments in which cystamine, a potent transglutaminase inhibitor, or small interfering RNA-mediated TG2 knockdown significantly attenuated autoantibody-induced hypertension and proteinuria in pregnant mice. Cystamine treatment also prevented isopeptide modification of placental AT1 receptors in preeclamptic mice. Mechanistically, we revealed that AT1-agonistic autoantibody stimulation enhances the interaction between AT1 receptor and TG2 and results in increased AT1 receptor stabilization via transglutaminase-mediated isopeptide modification in trophoblasts. Mutagenesis studies further demonstrated that TG2-mediated isopeptide modification of AT1 receptors prevents ubiquitination-dependent receptor degradation. Taken together, our studies not only identify a novel pathogenic involvement of TG2 in preeclampsia but also suggest a previously unrecognized role of TG2 in the regulation of G protein-coupled receptor stabilization by inhibiting ubiquitination-dependent degradation.

Concepts: Protein, Signal transduction, Enzyme, Angiotensin II receptor antagonist, Metabotropic glutamate receptor, Placenta, Angiotensin receptor, Angiotensin II receptor type 1

27

OBJECTIVE: To test whether long-term anti-hypertensive treatment with metoprolol succinate (a β1 -adrenoceptor blocker) or olmesartan medoxomil (an angiotensin II AT1 -receptor blocker) reverses microvascular dysfunction in hypertensive patients. METHODS: This study included 44 hypertensive outpatients and 20 age and sex-matched healthy controls. We used skin capillaroscopy to measure capillary density and recruitment at rest and during postocclusive reactive hyperemia (PORH). Endothelium-dependent vasodilation of skin microcirculation was evaluated with a laser Doppler perfusion monitoring system in combination with acetylcholine iontophoresis, PORH and local thermal hyperemia (LTH). RESULTS: Pretreatment capillary density in hypertensive patients was significantly reduced compared to controls (71.3±1.5 vs 80.6±1.8 cap/mm(2) ; p<0.001), as was PORH (71.7±1.5 vs 79.5±2.6 cap/mm(2) ; p<0.05). After treatment for six months, capillary density increased to 75.4±1.1 cap/mm(2) (p<0.01) at rest and 76.8±1.1 cap/mm(2) during PORH. During LTH, cutaneous vascular conductance (CVC) in perfusion units (PU)/mm Hg was similar in patients (1.71 [1.31-2.12]) and controls (1.60 [1.12-1.91]) and increased significantly (1.82 [1.30-2.20]) after treatment. Maximal CVC during PORH was reduced in hypertensive patients (0.30 [0.22-0.39]) compared to controls (0.39 [0.31-0.49], p<0.001) and increased (0.41 [0.29-0.51], p<0.001) after treatment. CONCLUSIONS: Capillary rarefaction and microvascular endothelial dysfunction in hypertensive patients responded favorably to long-term pharmacological treatment. This article is protected by copyright. All rights reserved.

Concepts: Hypertension, Endothelium, Angiotensin II receptor antagonist, Angiotensin receptor, Beta blocker, Copyright, Microcirculation, Metoprolol

27

Because growing evidence suggests that angiotensin II receptor blockers (ARBs) effectively inhibit oxidative stress, amyloid beta protein (Aβ) metabolism, and tau phosphorylation in animal brains, ARBs are considered to be a potential candidate for the treatment of Alzheimer’s disease (AD). Consistent with such basic studies, two recent observational studies and a small prospective, randomized, open-label trial have shown the effectiveness of ARBs in preventing AD and/or slowing its progression. Nonetheless, large clinical trials have not shown their effectiveness, but their results are debatable because of short follow-up durations and heterogeneity of the cognition assessments used in the studies. Because a recent analysis of the Honolulu-Asia Aging study showed that abnormalities of the serum Aβ level begin approximately 15 years before the diagnosis of AD, long-term clinical trials assessing dementia as a primary endpoint with sensitive measurements of cognition and brain imaging techniques will clarify the effectiveness of ARBs in AD treatment.

Concepts: Alzheimer's disease, Clinical trial, Brain, Angiotensin, Renin-angiotensin system, Angiotensin II receptor antagonist, Beta amyloid, Angiotensin receptor