The role of local and systemic renin angiotensin system activation in a genetic model of sympathetic hyperactivity-induced heart failure in mice.
Sympathetic hyperactivity (SH) and renin angiotensin system (RAS) activation are commonly associated with heart failure (HF), even though the relative contribution of these factors to the cardiac derangement is less understood. The role of SH on RAS components and its consequences for the HF were investigated in mice lacking alpha(2A) and alpha(2C) adrenoceptor knockout (alpha(2A)/alpha(2C)ARKO) that present SH with evidence of HF by 7 mo of age. Cardiac and systemic RAS components and plasma norepinephrine (PN) levels were evaluated in male adult mice at 3 and 7 mo of age. In addition, cardiac morphometric analysis, collagen content, exercise tolerance, and hemodynamic assessments were made. At 3 mo, alpha(2A)/alpha(2C)ARKO mice showed no signs of HF, while displaying elevated PN, activation of local and systemic RAS components, and increased cardiomyocyte width (16%) compared with wild-type mice (WT). In contrast, at 7 mo, alpha(2A)/alpha(2C)ARKO mice presented clear signs of HF accompanied only by cardiac activation of angiotensinogen and ANG II levels and increased collagen content (twofold). Consistent with this local activation of RAS, 8 wk of ANG II AT(1) receptor blocker treatment restored cardiac structure and function comparable to the WT. Collectively, these data provide direct evidence that cardiac RAS activation plays a major role underlying the structural and functional abnormalities associated with a genetic SH-induced HF in mice.
Ferreira
J C B
JC
School of Physical Education and Sport, Medical School, University of São Paulo, São Paulo, Brazil.
Bacurau
A V
AV
Evangelista
F S
FS
Coelho
M A
MA
Oliveira
E M
EM
Casarini
D E
DE
Krieger
J E
JE
Brum
P C
PC
D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D006333:Heart Failure / Q000503:physiopathology*; D006339:Heart Rate / Q000502:physiology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009638:Norepinephrine / Q000097:blood; D010805:Physical Conditioning, Animal; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000503:physiopathology*
C547769:Adra2a protein, mouse; C547775:Adra2c protein, mouse; D047228:Angiotensin II Type 1 Receptor Blockers; D018341:Receptors, Adrenergic, alpha-2; D000808:Angiotensinogen; D000804:Angiotensin II; D019808:Losartan; D009638:Norepinephrine