A Systematic Review to Investigate Whether Angiotensin-(1-7) Is a Promising Therapeutic Target in Human Heart Failure

Table 2

Studies in non-heart failure patients.

Study	Full publication or abstract	Disease and control population (if applicable)	Study type, for example, cohort/biopsy from patients/human cells	N	Key endpoint(s)	Key finding(s)
Ueda et al. [18]	Full	Healthy; normotensive	Cohort	22	Forearm blood flow (FBF)	Ang-(1-7) attenuates Ang II-induced vasoconstriction.
Campbell et al. [13]	Full	Coronary artery disease (CAD)	Cohort	20	Ang-(1-7) levels in coronary sinus and arterial blood (key endpoint of relevance to Ang-(1-7) )	No significant change in the level of Ang-(1-7) after acute intravenous administration of an ACE inhibitor.; On an assumed haematocrit of 45%, net Ang-(1-7) formation by the heart was unchanged after ACE inhibitor administration.
Ferrario et al. [33]	Full	Healthy volunteers and essential hypertension (HTN)	Cohort	Healthy volunteers (𝑛=31), essential HTN (𝑛=18)	Urinary concentration of Ang-(1-7)	Urinary Ang-(1-7) correlated inversely with arterial pressures; reduced levels in untreated essential HTN patients.
Roks et al. [34]	Full	Patients undergoing coronary artery bypass grafting (CABG) surgery and healthy donors	Biopsies	CABG (𝑛=25), healthy donor (𝑛=1)	Plasma/tissue ACE activity and contractile function in human arteries	Ang-(1-7) blocks arterial vasoconstriction and inhibits ACE in plasma, atrial and arterial, tissues.
Wilsdorf et al. [19]	Full	Healthy subjects	Cohort	8	FBF; endothelial TPA release	Ang-(1-7) had no significant effect on the endpoints.
Pan et al. [35]	Full	NA	Primary cultures of human cardiac (HC) myocytes and HC fibroblasts	NA	Transcription of matrix metalloproteinase (MMP)−1, −2, and −9, and tissue inhibitors of matrix metalloproteinase (TIMP) −1, −2, and −3	Ang-(1-7) and Ang II have opposing and antagonistic effects.; Ratios of MMPs to TIMPs were decreased (suggestive of less myocardial fibrosis) by Ang-(1-7).
Sampaio et al. [36]	Full	NA	Human aortic endothelial cells (HAECs)	NA	Activation of NAD(P)H oxidase; phosphorylation of extracellular signal regulated kinase (ERK)1/2; c-Src activation; SHP-2 phosphorylation; c-Src and SHP-2 interaction	Ang II signalling is counter-regulated by Ang-(1-7); effects are mediated probably via Mas.
Rajendran et al. [37]	Full	Normal subjects and patients with acute coronary syndrome (ACS)	Cohort study	Normal (𝑛=17) ACS (𝑛=17)	Platelet aggregation and responsiveness	Ang-(1-7) reduces platelet aggregation by potentiating sodium nitroprusside.
Peltonen et al. [38]	Full	Aortic regurgitation (AR); AR plus fibrosis (AR+F); aortic stenosis (AS); normal valve (control)	Cohort	Control (𝑛=11); AR (𝑛=14); AR + F (𝑛=20); AS (𝑛=61)	Expression of Mas receptor (key endpoint of relevance to Ang-(1-7))	Mas receptor mRNA levels in stenotic valves were lower than control, AR, and AR+F valves, further supporting the hypothesis that myocardial fibrosis is attenuated by Ang-(1-7), an endogenous Mas receptor agonist.
Christofi et al. [39]	Abstract	NA	Human saphenous vein cells (hSVSMC); human coronary artery cells (hCAC) and saphenous vein cells (hVTSM1)-derived immortalised human VSMC	NA	PCR on complimentary DNA expression of the Mas receptor (key endpoint of relevance to Ang-(1-7))	Mas gene expression was not detected in these cells.
Sampaio et al. [40]	Full	NA	Human aortic endothelial cells (HAECs)	NA	NO synthase (eNOS) expression/activity; role of Mas; regulation of ser1179 and thr495 phosphorylation sites of NO synthase; role of the phosphatidylinositol 3-kinase (PI3K)/Akt-pathway	HAECs express Mas and via this receptor mediate the activation of eNOS.; eNOS activation and NO release by Ang-(1-7) involve the role of the PI3K/Akt pathway.
Lin et al. [41]	Full	NA	Human cardiac fibroblasts	NA	ACE2 mRNA and protein expression; phosphorylated ERK1/2 (p-ERK1/2) protein expression	Ang-(1-7) upregulates ACE2 expression, possibly independent of the Ang II-Angiotensin type 1 receptor signalling pathway.; A positive feedback loop is observed (Ang-(1-7) increases ACE2 expression in vitro; increased ACE2 could promote more Ang-(1-7)).
Schindler et al. [42]	Full	Healthy young male nonsmokers	Cohort	8	Ang-(1-7) peptide level (determined relevant from the results section)	Irbesartan significantly increased Ang-(1-7) peptide levels.; Atorvastatin had no effect on the Ang-(1-7) peptide level.
Rajendran et al. [43]	Full	NA	Whole blood	NA	Ang-(1-7) effect on NO responsiveness of platelets; is this associated with the modulation of O2^−  release? Role of a specific Ang-(1-7) receptor	Effects of Ang-(1-7) occurred only in whole blood (another experiment was done on platelet-rich plasma).; The antiaggregatory effects of the NO donor sodium nitroprusside (SNP) were potentiated by Ang-(1-7), probably by a specific Ang-(1-7) receptor.; O2^− release suppression by SNP was potentiated by Ang-(1-7).
Ueda et al. [44]	Full	Healthy normotensive	Cohort	Procedure 1 (𝑛=8); procedure 2 (𝑛=8); procedure 3 (𝑛=6 out of 8 from procedure 2)	FBF	Ang-(1-7) in a dose-dependent manner potentiated the vasodilating effect of BK (doses of 1000 pmol/min and 100 pmol/min).; Abolishing effects of an NO synthase inhibitor were not statistically significant.; There was no effect of Ang-(1-7) on the vasodilating effects of either acetylcholine or SNP.
Gironacci et al. [45]	Full	NA	Mas receptor-yellow fluorescent protein (MasR-YFP) transfected human embryonic kidney 293T cells	Na	Relative cellular distribution of MasR-YFP	Ang-(1-7) causes the MasR to undergo endocytosis.
Luque et al. [46]	Full	Essential HTN	Cohort	24	Plasma concentration of Ang-(1-7) in the peripheral venous blood (key endpoint of relevance to Ang-(1-7))	The last dose of captopril (6 months after) produced significantly greater levels of Ang-(1-7).; There was a negative correlation between plasma Ang-(1-7) and diastolic blood pressure in a subset of essential HTN subjects (in whom BP was controlled with captopril only).
Hayashi et al. [47]	Full	NA	Smooth muscle cells and endothelial cells	NA	ERK1/2 phosphorylation; smooth muscle cell proliferation; adhesion of monocytes to endothelial cells.	D-Ala (Mas antagonist) pretreatment decreased the inhibitory effect of olmesartan (in response to Ang II stimulation).; Ang II increased the endpoints which olmesartan inhibited.
Zisman et al. [48]	Full	Orthotopic heart transplantation recipients (normal coronary anatomy and left ventricular function)	Cohort	4	^123I-Ang-(1-7) was quantified in the myocardial circulation.	Ang-(1-7) is produced in the myocardial circulation.; Reduced levels of Ang II (via enalaprilat) caused levels of Ang-(1-7) to decrease.
Gallagher and Tallant [49]	Full	NA	Lung adenocarcinoma cells; adenocarcinoma cells; squamous cell; carcinoma cells	NA	Cell number; DNA synthesis; inhibition time course of DNA synthesis by Ang-(1-7); Mas mRNA; DNa replication; ERK1/2 activities	Lung cancer cell growth is inhibited by Ang-(1-7), possibly via the activation of an Angiotensin peptide receptor, which may involve the ERK signal transduction pathway.
Pignone et al. [50]	Full	Systemic sclerosis (SSc); control subjects	Cohort	SSc (𝑛=32); control (𝑛=55)	Ang-(1-7), neutral endopeptidase (NEP), NO and prostaglandin I2 (PGI2) levels	Lower Ang-(1-7) levels were detected in patients with SSc.; The Ang II/Ang-(1-7) ratio in SSc patients showed greater Ang II levels to Ang-(1-7).; In the controls, Ang-(1-7) was prevalent.; NEP, NO, and PGI2 levels are reduced in the SSc group.
Silva et al. [51]	Full	HTN (12 renovascular; 15 essential HTN); normotensive subjects; paediatric population	Cohort	Renovascular HTN (𝑛=12); essential HTN (𝑛=15); normotension (𝑛=32)	Ang-(1-7) levels in the blood (key endpoint of relevance to Ang-(1-7))	Ang-(1-7) levels are significantly higher in HTN (renovascular) patients compared to normal children.; In the essential HTN subjects, Ang-(1-7) levels were significantly increased compared with normotensive subjects.; Calcium channel blockers had no effect on the RAAS measurements.
Simões E Silva et al. [52]	Full	Normotensive healthy subjects; normotensive chronic renal failure (CRF); hypertensive CRF; end-stage renal disease (ESRD)	Cohort	Normotensive healthy subjects (𝑛=32); normotensive CRF (𝑛=23); hypertensive CRF (𝑛=34); ESRD (𝑛=21)	Radioimmunoassays for Ang-(1-7) levels (key endpoint of relevance to Ang-(1-7))	In the hypertensive CRF subjects, Ang-(1-7) levels were higher compared with normotensive CRF and healthy subjects.; There was no difference between normotensive CRF and healthy subjects.
Nickenig et al. [53]	Full	NA	Human skin fibroblasts (from a skin biopsy; purchased)	NA		Ang-(1-7) competed for the Ang II binding, causing 80% loss of binding activity (approximately).; Ang-(1-7) may be involved in DNA synthesis.; Effects of Ang-(1-7) may be mediated via the Mas receptor.
Anton et al. [54]	Full	NA	Human umbilical vein endothelial cells (HUVECs)	NA	Tube formation of HUVECs	Ang-(1-7) exerted inhibitory effects on HUVEC tube formation.; The effect of Ang-(1-7) was reversed by A779.; Losartan also reversed the Ang-(1-7) mediated inhibition (similarly as to A779).
Villalobos et al. [55]	Abstract	NA	Cultured human vascular smooth muscle cells (HASMC)	NA	Levels of inducible NO synthase (iNOS) and NO release	Ang-(1-7) acts via Mas receptor and partially prevented vascular smooth muscle inflammation
Montezano et al. [56]	Abstract	NA	Cultured human microvascular endothelial cells (HMEC)	NA	Expression of a proinflammatory mediator, cell growth marker, and ET𝐵receptor.ET𝐴 receptor gene expression	Proinflammatory and mitogenic actions of ET−1/ET𝐴 receptor were negatively modulated by Ang-(1-7).
Peltonen et al. [57]	Abstract	Normal valves (control); AR; AR+F; AS	Cohort	Control (𝑛=11); AR (𝑛=11); AR+F(𝑛=17); AS (𝑛=57)	Expression of the Mas receptor in aortic valves (key endpoint of relevance to Ang-(1-7))	The Mas receptor is downregulated in stenotic aortic valves.; Mas gene expression is not affected by statin treatment in the AS group.
Zhiming et al. [58]	Abstract	NA	THP-1 derived macrophages (human)	NA	mRNA and protein expression of ATP-binding cassette transporter A1 (ABCA1); macrophage cholesterol efflux	Decreased THP-1 induced macrophage cholesterol efflux, and ABCA1 expression by Ang II was reversed by Ang-(1-7) in a dose-response relationship.; A-779 (Ang-(1-7) Mas receptor antagonist) had no effect on the endpoints.
Vzquez-Bella et al. [59]	Abstract	NA	Cultured human umbilical endothelial veins (HUVECs)	NA	Endothelial nitric oxide synthase (eNOS) and NO levels; L-arginine (eNOS substrate) asymmetric dimethylarginine (ADMA) (eNOS inhibitor); expression of ICAM-1 and VCAM-1 (cell adhesion molecules)	Ang-(1-7) pretreatment increased the NO release mediated by BK, an effect inhibited by A779 pre-treatment.; Pretreatment with A779 increases levels of the inactive phosphorylated (Thr 495) form of eNOS and reduces the L-arginine/ADMA ratio.; There was no effect of Ang-(1-7) on VCAM-1 and ICAM-1 expressions in nonstimulated (non-Ang II) HUVECs.; There was reduced induction of ICAM-1 and VAM-1 in stimulated cells.
Santos; et al. [60]	Abstract	NA	Confluent cultured human aortic and umbilical vein endothelial cells	NA	Formation of Ang-(1-7)	Generation of  ^125I-Angiotensin-(1-7) was time dependent when incubated with ^125I-Angiotensin I.
Hermenegildo et al. [61]	Abstract	NA	Human umbilical vein endothelial cells (HUVECs)	NA	Expression of mRNA and protein of the enzymes associated with Ang-(1-7) production and NO synthesis	Oestradiol (E2) increased the expression of enzymes implicated in the production of NO and NO receptor expressions. A779 abolished E2’s effect on NO synthase and NO receptor expression.; A779 inhibited NO levels (NO levels increased by E2).
Kono et al. [62]	Full	Normal men and Bartter syndrome (BS)	Cohort	Normal (𝑛=5); BS (𝑛=3)	BP; aldosterone and plasma renin (key endpoint of relevance to Ang-(1-7))	A significant increase in BP was observed in normal men after Ang-(1-7) infusion.; After the infusion of Ang-(1-7), it took 20 min (for systolic) and 30 min (for diastolic) for the pressor actions to cease.; In patients with BS, Ang-(1-7) had no effect.; Ang-(1-7) had no effect on aldosterone; however, it did lower plasma renin activity in both normal and BS groups.; Ang-(1-7) has pressor actions, however, having effects <0.03% of Ang II.
Sasaki et al. [63]	Full	Essential HTN and normotensive controls	Cohort	Normotension (𝑛=8); essential HTN (𝑛=8)	FBF	Ang-(1-7) increases FBF through NO independent manner.
Calò et al. [64]	Full	Bartter syndrome/Gitelman syndrome* (BS/GS); normotensive healthy subjects; essential HTN	Cohort	BS/GS (𝑛=10); normotensive healthy subjects (𝑛=10); untreated essential HTN (𝑛=10)	Levels of ACE2 and Ang-(1-7)	Ang-(1-7) levels are elevated in BS/GS patients compared with the other two groups.; In BS/GS patients, there was a direct correlation between ACE2 and Ang-(1-7).; This study provides further support of the hypothesis that Ang-(1-7) regulates vascular tone.

*In Bartter syndrome/Gitelman syndrome, patients have gene defects in specific kidney transporters and ion channels, resulting in raised plasma Ang II and aldosterone, but intriguingly, they have normal or even low blood pressure. Their peripheral resistance is reduced, and they exhibit hyporesponsiveness to pressors.