Exaggerated blood pressure variability superimposed on hypertension aggravates cardiac remodeling in rats via angiotensin II system-mediated chronic inflammation.
Hypertensive patients with large blood pressure variability (BPV) have aggravated end-organ damage. However, the pathogenesis remains unknown. We investigated whether exaggerated BPV aggravates hypertensive cardiac remodeling and function by activating inflammation and angiotensin II-mediated mechanisms. A model of exaggerated BPV superimposed on chronic hypertension was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). SAD increased BPV to a similar extent in Wistar Kyoto rats and SHRs without significant changes in mean blood pressure. SAD aggravated left ventricular and myocyte hypertrophy and myocardial fibrosis to a greater extent and impaired left ventricular systolic function in SHRs. SAD induced monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen mRNA upregulations and macrophage infiltration of the heart in SHRs. The effects of SAD on cardiac remodeling and inflammation were much smaller in Wistar Kyoto rats compared with SHRs. Circulating levels of norepinephrine, the active form of renin, and inflammatory cytokines were not affected by SAD in Wistar Kyoto rats and SHRs. A subdepressor dose of candesartan abolished the SAD-induced left ventricular/myocyte hypertrophy, myocardial fibrosis, macrophage infiltration, and inductions of monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen and subsequently prevented systolic dysfunction in SHRs with SAD. These findings suggest that exaggerated BPV induces chronic myocardial inflammation and thereby aggravates cardiac remodeling and systolic function in hypertensive hearts. The cardiac angiotensin II system may play a role in the pathogenesis of cardiac remodeling and dysfunction induced by a combination of hypertension and exaggerated BPV.
Kudo
Hiroshi
H
Department of Internal Medicine, Division of Cardio-Vascular Medicine, Kurume University School of Medicine, 67 Asahimachi, Kurume, Japan.
Kai
Hisashi
H
Kajimoto
Hidemi
H
Koga
Mitsuhisa
M
Takayama
Narimasa
N
Mori
Takahiro
T
Ikeda
Ayami
A
Yasuoka
Suguru
S
Anegawa
Takahiro
T
Mifune
Hiroharu
H
Kato
Seiya
S
Hirooka
Yoshitaka
Y
Imaizumi
Tsutomu
T
D000804:Angiotensin II / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000502:physiology*; D018932:Chemokine CCL2 / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D006331:Heart Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology*; D006984:Hypertrophy / Q000473:pathology / Q000517:prevention & control; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013777:Tetrazoles / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D000808:Angiotensinogen; D000804:Angiotensin II; C081643:candesartan