Table 1.
A summary of the beneficial role of MasR in relation to coronary atherosclerosis risk factors.
| Risk factor | MasR agonist or antagonist (Dose/Route/Duration) | Study design | Results | Reference | |
|---|---|---|---|---|---|
| Hypertension | Ang 1–7 | 1 to 100 nmol.kg−1/IV/before and during the first and third weeks after onset of renovascular hypertension | Dogs | ↑vasodilator component of the blood pressure response; ↓hypertensive dogs fed the NOS inhibitor; synergistic effect with endothelium-derived relaxing factors to buffer the increase in vascular resistance produced by chronic renal ischemia | (119) |
| AVE-0991 Ang 1–7 |
10−7 M/PO in the drinking water/for the last 3 days 29 μM·kg−1·h−1/IV/continuous infusion for the last 3 days |
Sprague-Dawley rats | no significant effect on body weight or arterial blood pressure; restore endothelium-dependent vascular relaxation; ↑superoxide levels in rats fed a high-salt diet, but the expression of Cu/Zn SOD and Mn SOD enzyme proteins in the vessel wall was unaffected; ↓vascular oxidant stress and enhancing NO availability | (120) | |
| Ang 1–7 | 576 μg·kg−1·day−1/IV/infused via a mini-osmotic pump for 4 weeks | Sprague-Dawley rats | ↓hypertension and cardiac hypertrophy (only in trained 2K1C rats but not in sedentary 2K1C rats); ↓myocyte diameter and cardiac fibrosis | (121) | |
| Ang 1–7 | 10−10, 10−9, or 10−8 M/min/IA/ infused for 5 minutes |
Human (Clinical trial) |
↑forearm blood flow response in a dose-dependent manner; vasodilatory effect that is independent of NOS | (122) | |
| Ang 1–7 | 10−6 M/in tissue bath | Sprague-Dawley rats | ↑endothelium-dependent and NO-mediated relaxation; unmasked vasodilator responses to bradykinin; ↑ BK and Ach responses; restoring endothelial function impaired by elevated dietary salt intake | (123) | |
| Ang 1–7 | 50–250 ng/ intra-hypothalamic/stabilization period of 30 min |
Wistar Kyoto rats Spontaneously hypertensive rats |
not the change basal MAP; co-administration of Ang-(1–7) with Ang II did not affect the pressor response; not participate in the hypothalamic blood pressure regulation pleiotropic effects on blood pressure regulation (high dose of the heptapeptide produced a pressor response by ↑activation of AT1 receptors and lower doses of Ang-(1–7) with Ang II ↓the pressor response to the octapeptide) |
(124) | |
| Ang 1–7 | 200 ng.h−1/ intra-cerebroventricular/ for 14 days |
Sprague-Dawley rats | improvement of baroreflex control of HR; normalized mRNA expression of collagen type I in the left ventricle; balance of cardiac autonomic tone; ↓ MAP; no effect on circulating or cardiac changes in angiotensin levels | (125) | |
| Ang 1–7 | 1.8 μg.h−1/ intra-cerebroventricular/for 6 weeks |
Dahl salt-sensitive rats | ↑NO level; ↓sympathetic activity; ↓blood pressure; ↓cardiac hypertrophy; regulates neurotransmitter levels; ↑expression of GABA and GAD67; expression of norepinephrine, glutamate and tyrosine hydroxylase | (126) | |
| A-779 | 3 nM/ intra-paraventricular |
Sprague-Dawley rats | ↑ MAP; ↑renal sympathetic nerve activity (RSNA); ↑plasma norepinephrine; ↑level of IL-1β, IL-6 and TNF-α; ↑MCP-1, gp91phox expression and superoxide production; ↑oxidative stress | (127) | |
| AVE-0991 | 20 mg/kg/day/PO/ for 5 weeks |
Spontaneously hypertensive rats | ↓heart rate and blood pressure variability (HRV, BPV); ↓spontaneous baroreceptor sensitivity (BRS); ↓baroreflex fluctuations; influence on the circadian rhythm | (128) | |
| Ang 1–7 | 1.8 μg.h−1/ intra-cerebroventricular/ for 4 weeks |
Sprague-Dawley rats | ↓expression of several renin-angiotensin system components, estrogen receptors and an NADPH oxidase; ↓Aldo/NaCl pressor effect | (131) | |
| Ang 1–7 AVE-0991 |
24 μg.kg−1.h−1/IP/ for 4 weeks |
Wistar-Kyoto rats Spontaneously hypertensive rats |
↓MAP; ↓proteinuria; ↓abnormal vascular responsiveness to endothelin-1; recovery of cardiac function; ↓development of severe hypertension and end-organ damage; ↓cardiac ischemia | (132) | |
| Ang 1–7 | 100 ng.kg−1.min−1/implanted mini-osmotic pump/for 4 weeks | Sprague-Dawley rats | ↓collagen deposition effects; prevents cardiac fibrosis and cardiac remodeling independent of blood pressure or cardiac hypertrophy; not significantly ↓blood pressure | (133) | |
| Ang 1–7 | 24 μg.kg−1.h−1/IP/ for 14 days |
Wistar-Kyoto rats Spontaneously hypertensive rats |
no effects on blood pressure; down-regulated cardiac Mas mRNA and renal Mas mRNA; ↓Cardiac and renal ACE2 mRNA; not change renal ACE2 | (134) | |
| A-779 | 1 mg.day−1/implanted SC/ for 4 weeks |
Sprague-Dawley rats | ↑cardiac inflammation and fibrosis; ↑apoptotic responses; no effects on cardiac function; MasR expressions in the hypertensive heart and kidney are not regulated by circulating AngII levels | (135) | |
| AVE-0991 | 20 mg.kg−1.day−1/PO/ for 4 weeks |
C57BL/6J mice | ↓mean myocyte diameter; ↓gene expression of the hypertrophic markers; ↓expression of NOX 2 and NOX; ↓oxidative stress; ↓cardiac hypertrophy; improve heart function; ↓left ventricular weight and left ventricular end-diastolic diameter | (136) | |
| Ang 1–7 | 576 μg·kg−1·day−1 /IP/ for 4 weeks |
Sprague-Dawley rats | not modify the increase in blood pressure; ↓development of myocardial fibrosis and hypertrophy; ↓myocardial inflammatory cell infiltration and tyrosine hydroxylase expression | (137) | |
| Dyslipidemia | Ang 1–7 | 0.1 mg.kg−1/PO/ for 4 weeks |
FVB/N mice | ↓body weight and food intake; ↓blood parameters such as total cholesterol, triglyceride, alanine transaminases, and aspartate transaminases; ↓proinflammatory profile such as expression of IL-6 and TNF-α; ↓acetyl-CoA carboxylase, PPARγ, and SREBP-1c mRNA expression | (100) |
| Transgenic rats overexpressing Ang 1–7 | ↓ LPL expression; ↑ PPARγ expression; ↓adiposity index and lipogenesis independent of the stimulatory effect of insulin; ↓concentration of triacylglycerol in the liver; ↑activity of cytosolic lipases; ↓fatty acid uptake from the adipose tissue | (101) | |||
| Diabetes mellitus | Ang 1–7 | 300 μg·kg−1·day−1/SC/ for 8 weeks |
Wistar rats | ↓body weight; ↓blood glucose levels; ↓fasting serum Ang II levels; ↑fasting serum insulin levels and facilitated insulin production; ↓homeostasis model assessment of insulin resistance (HOMA-IR); ↓ iNOS, caspase-3, caspase-9, caspase-8, Bax and reduction of Bcl-2; ↑improvement of insulin resistance, insulin secretion, and pancreatic cell survival | (147) |
| Ang 1–7 | 50 μg·kg−1·day−1/SC/ for 48 days |
C57BL/6J mice | ↑insulin level; ↓blood glucose levels; ↓glycated hemoglobin levels; improves oral glucose tolerance; no significantly weight loss | (8) | |
| Ang 1–7 | 576 μg·kg−1·day−1/IP/ for 4 weeks |
Wistar rats | ↓abnormal vascular reactivity to endothelin-1 and cardiac dysfunction; improvement in cardiac recovery or vascular reactivity; ↓NOX activity and end-organ damage | (148) | |
| AVE0991 | 20 mg·kg−1·day−1/PO/ for 5 weeks |
Sprague-Dawley rats | no effect on any of the investigated hemodynamic parameters under normoglycemic conditions; ↓cardiac function; normalization of blood pressure and contractility parameters; protective effect on the diabetic heart | (153) | |
| Ang 1–7 | Wistar rats | ↓fasting blood glucose; ↓serum angiotensin II level; ↓HOMA-IR value; ↑serum insulin level; ↑insulin secretion; ↓insulin resistance and islet fibrosis; upregulation of Pdx1, Glut2 and Gk expressions | (154) | ||
| Ang 1–7 | 1–10 µM/for 24 h | RINm5F cell | ↑ CREB activation; ↑intracellular cAMP; ↑CFTR expression; ↑glucose-stimulated insulin secretion | (155) | |
| Ang 1–7 | Wistar rats | ↓cleaved caspase 3 levels in pancreas; ↓expression of JNK, Bax, and Bcl2 genes; ↑islet function and histopathology; reversed high glucose (HG)-induced mitochondrial apoptosis augments; improved the islet β-cells apoptosis by JNK-mediated mitochondrial dysfunction | (156) | ||
| Ang 1–7 | 30 µg.kg−1/PO/ on days 28 to 36 then 100 µg.kg−1/ on days 57 to 72 |
Tet29 rats | ↑improved glucose uptake; ↓blood glucose levels; ↑improved insulin sensitivity; ↓ plasma insulin; ↓diabetic nephropathy | (157) | |
| Ang 1–7 | 1 µM.L−1/for 24 h | H9c2 cell culture | ↓overexpression levels of leptin; ↓p-p38 MAPK and ERK1/2, but not p-c-Jun N-terminal kinase; ↑cell viability; ↓apoptotic rate; ↓ROS production; ↑mitochondrial membrane potential | (158) | |
| Ang 1–7 | bEnd3 cell culture | ↓HG-induced endothelial injury through downregulating CIC-3; ↓productions of ROS and cytokine such as IL-1β, IL-8, IL-6, NF-κB and TNF-α; ↓ NO level | (159) | ||
| Ang 1–7 | 1, 10, 100 and 1000 pM | Wistar rats | not potentiate bradykinin-induce vasodilation in diabetic rats; ↑vasodilatory effect; restoring effect via mechanism involving membrane hyperpolarization but not NO release | (160) | |
| Ang 1–7 | 576 μg·kg−1·day−1/IP/ for 4 weeks |
Wistar Kyoto rats Spontaneously hypertensive rats |
↓renal NADPH oxidase activity; ↓renal vascular dysfunction; ↓renal catalase, and PPAR-γ levels; ↓degree of proteinuria and hyperglycemia, but had little or modest effect on reducing mean arterial pressure; ↑renal vascular responsiveness to endothelin-1 | (163) | |
| Obesity | Transgenic rats overexpressing Ang 1–7 | regulated food intake and body weight; ↓weight after AT1 receptor blockade; ↑ insulin response to OGTT and ↓insulin resistance; ↓energy intake; remained responsive to leptin | (164) | ||
| Ang 1–7 | 0.54 mg kg−1 day−1/implanted SC/for 28 days | C57BL/6J mice | ↓body weight and lipid accumulation; ↑thermogenesis; ↓impaired glucose homeostasis; ↑expression of UCP1, PRDM16, and prohibitin; ↑AMPK and phosphorylation of mTOR; preserved insulin signaling concomitant with phosphorylation of hormone-sensitive lipase; ↓expression of perilipin; improved metabolic profile | (7) | |
| Ang 1–7 | 100 μg.kg−1/PO/ for 8 weeks |
Sprague-Dawley rats | ↓body weight and abdominal fat-mass; ↑glucose tolerance; ↑insulin-sensitivity; ↓plasma-insulin levels; ↓circulating lipid levels (cholesterol, HDL and triglycerides); ↓expression of resistin, TLR4, ACE and ↑ACE2 expression in liver; ↓phosphorylation of MAPK and NF-κB expression; ↓expression of IL-6 and TNF-α | (168) | |
| Ang 1–7 | 100 μg/locally in the striatum through the micro-dialysis probe/ for 8 weeks |
Sprague-Dawley rats | ↑extracellular dopamine and GABA but had no effect on glutamate release; ↑GABA release by the NOS inhibitor L-NAME | (167) | |
| Ang 1–7 | 10 nM.min−1/IA/ infused for 5 minutes |
Human (Clinical trial) |
↑unstimulated forearm flow; ↑improve insulin-stimulated endothelium-dependent vasodilation; ↓endothelin-1–dependent vasoconstrictor tone | (169) | |
| Ang 1–7 | 0.4 μg.kg−1.min−1/SC/ for 4 weeks |
C57BL/6J mice | improves Ang II-induced vascular dysfunctions; ↑endothelial-dependent vasodilatation by increased Ach-induced relaxation; ↑aortic expression of NAD(P)H oxidase subunits (p22phox and p47phox) and plasma TBARS; not affect arterial pressure and heart rate; not normalize the altered contractions | (170) | |
| Transgenic rats overexpressing Ang 1–7 | ↓body weight, ↓heart weight to femur length ratio | (171) | |||