Guanylyl cyclase-A inhibits angiotensin II type 1A receptor-mediated cardiac remodeling, an endogenous protective mechanism in the heart.
BACKGROUND
Guanylyl cyclase (GC)-A, a natriuretic peptide receptor, lowers blood pressure and inhibits the growth of cardiac myocytes and fibroblasts. Angiotensin II (Ang II) type 1A (AT1A), an Ang II receptor, regulates cardiovascular homeostasis oppositely. Disruption of GC-A induces cardiac hypertrophy and fibrosis, suggesting that GC-A protects the heart from abnormal remodeling. We investigated whether GC-A interacts with AT1A signaling in the heart by target deletion and pharmacological blockade or stimulation of AT1A in mice.


RESULTS
We generated double-knockout (KO) mice for GC-A and AT1A by crossing GC-A-KO mice and AT1A-KO mice and blocked AT1 with a selective antagonist, CS-866. The cardiac hypertrophy and fibrosis of GC-A-KO mice were greatly improved by deletion or pharmacological blockade of AT1A. Overexpression of mRNAs encoding atrial natriuretic peptide, brain natriuretic peptide, collagens I and III, transforming growth factors beta1 and beta3, were also strongly inhibited. Furthermore, stimulation of AT1A by exogenous Ang II at a subpressor dose significantly exacerbated cardiac hypertrophy and dramatically augmented interstitial fibrosis in GC-A-KO mice but not in wild-type animals.


CONCLUSIONS
These results suggest that cardiac hypertrophy and fibrosis of GC-A-deficient mice are partially ascribed to an augmented cardiac AT1A signaling and that GC-A inhibits AT1A signaling-mediated excessive remodeling.
Li
Yuhao
Y
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kishimoto
Ichiro
I
Saito
Yoshihiko
Y
Harada
Masaki
M
Kuwahara
Koichiro
K
Izumi
Takehiko
T
Takahashi
Nobuki
N
Kawakami
Rika
R
Tanimoto
Keiji
K
Nakagawa
Yasuaki
Y
Nakanishi
Michio
M
Adachi
Yuichiro
Y
Garbers
David L
DL
Fukamizu
Akiyoshi
A
Nakao
Kazuwa
K
D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000808:Angiotensinogen / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis / Q000235:genetics; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D005355:Fibrosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D018390:Gene Targeting; D006162:Guanylate Cyclase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006339:Heart Rate / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006973:Hypertension / Q000235:genetics / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis / Q000235:genetics; D000068557:Olmesartan Medoxomil; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017461:Receptors, Atrial Natriuretic Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D000808:Angiotensinogen; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D000068557:Olmesartan Medoxomil; D009320:Atrial Natriuretic Factor; D003094:Collagen; D007703:Peptidyl-Dipeptidase A; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A