G protein-coupled estrogen receptor (GPER) activation by G1 attenuates diastolic dysfunction
from estrogen loss, which may be partly due to suppression of angiotensin II pathological
actions. We aimed to determine the independent effects of 8 weeks of G1 (100 µg/kg/d,
subcutaneous pellet), ACE-inhibition (ACEi; lisinopril 10 mg/kg, drinking water),
or combination therapy versus vehicle in the ovariectomized (OVX) spontaneously hypertensive
rat (SHR) on cardiac function and morphometrics (echocardiography), serum equilibrium
of angiotensins (mass spectroscopy) and cardiac components of the RAS (Western blotting).
G1 alone and when combined with ACEi enhanced myocardial relaxation (é: 30 and 17%)
and diastolic wall strain (DWS: 76 and 68%) while reducing relative wall thickness
(RWT: 20 and 33%) and filling pressures (E/é: 30 and 37%). Cardiac expression levels
of Mas receptor (Mas-R) and ACE2 also increased in the presence of G1. Strong antihypertensive
effects of lisinopril monotherapy were associated with reductions in RWT, collagen
deposition and E/é without overtly altering é or DWS. Chronic ACEi also increased
cardiac levels of Mas-R and AT1-R and tilted the circulating RAS toward the formation of Ang-(1–7), which was amplified
in the presence of G1. In vitro studies further revealed that an inhibitor to prolyl endopeptidase (PEP), but not
to neprilysin, significantly reduced serum Ang-(1–7) levels in G1-treated rats, suggesting
that G1 might be increasing Ang-(1–7) formation via PEP. We conclude that activating
GPER with G1 augments components of the cardiac RAS and improves diastolic function
without lowering blood pressure, and that lisinopril-induced blood pressure control
and cardiac alterations in OVX SHR are permissive in facilitating G1 to augment Ang-(1–7)
in serum, thereby strengthening its cardioprotective benefits.
Abbreviations:
ACE (angiotensin converting enzyme), ACE2 (angiotensin-converting enzyme 2), ACEi (angiotensin converting enzyme inhibitor), ADAM (a disintegrin and metalloprotease domain 17), AmP (aminopeptidase), Ang I (angiotensin I), Ang II (angiotensin II), Ang-(1-7) (angiotensin-(1-7)), Ang-(1-12) (angiotensin-(1-12)), AP (angiotensin peptide), AT1-R (angiotensin II receptor type 1), AWT (anterior wall thickness), AWTed (anterior wall thickness end diastole), COL1A1 (collagen type 1 alpha 1 chain), COL3A1 (collagen type III alpha 1 chain), DAP (aspartyl aminopeptidase), DWS (diastolic wall strain), FS (fractional shortening), GPER (G protein-coupled estrogen receptor), Lis (lisinopril), LV (left ventricular), LVEDD (left ventricular end-diastolic dimension), LVEF (left ventricular ejection fraction), LVESD (left ventricular end-systolic dimension), Mas-R (Mas receptor), NEP (neprilysin or neutral endopeptidase), OVX (ovariectomy), PEP (prolyl endopeptidase), PWT (posterior wall thickness), PWTed (posterior wall thickness end-diastole), PWTes (posterior wall thickness end-systole), RAS (renin-angiotensin system), RWT (relative wall thickness), SBP (systolic blood pressure), SHR (spontaneously hypertensive rat), THOP (thimet oligopeptidase 1), Veh (vehicle), ZPP (Z-prolyl prolinal)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: April 25, 2021
Accepted:
April 13,
2021
Received in revised form:
April 7,
2021
Received:
November 18,
2020
Identification
Copyright
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