Molecular mechanism of aggravation of hypertensive organ damages by short-term blood pressure variability

Abstract

There is increasing evidence that not only the elevation of systolic and diastolic blood pressure (BP) but also the increase in BP variability (or fluctuation) are associated with hypertensive organ damages and the morbidity and mortality of cerebrovascular and cardiovascular events. However, the molecular mechanism whereby the increase in BP variability aggravates hypertensive organ damages remains unknown. Thus, we created a rat chronic model of a combination of hypertension and large BP variability by performing bilateral sino-aortic denervation in spontaneously hypertensive rat. A series of our studies using this model revealed that large BP variability induces chronic myocardial inflammation by activating local angiotensin II and mineralocorticoid receptor systems and thereby aggravates cardiac hypertrophy and myocardial fibrosis, leading to systolic dysfunction, in hypertensive hearts. In addition, large BP variability induces the aggravation of arteriolosclerotic changes and ischemic cortical fibrosis in hypertensive kidney via local angiotensin II system.

Fig. (1)

Regulating factors of blood pressure variability

Fig. (2)

Chronic model of a combination of hypertension and large blood pressure variability. A. 24-h records of mean blood pressure (mBP) under the unrestricted, conscious condition. B. Representative microphotographs of Mallory-Azan-stained left ventricles. C. Pooled data of changes in myocyte diameter (a), %myocardial fibrosis area (b), and left ventricular (LV) fractional shortening (c). WKY, Wistar Kyoto rat; SHR, spontaneously hypertensive rat; SAD, bilateral sino-aortic denervation. Modified from Kudo et al [20].

Fig. (3)

Scheme of the inflammatory changes in a rat model of hypertensive heart with diastolic, but not systolic, dysfunction induced by abdominal aortic constriction. ACE, angiotensin-converting enzyme; MCP-1, macrophage chemoattractant factor-1; TGF-β, transforming growth factor-β. Modified from Kai et al [29].

Fig. (4)

Scheme of the inflammatory changes in a rat model of hypertensive heart with diastolic, but not systolic, dysfunction induced by abdominal aortic constriction. ACE, angiotensin-converting enzyme; MCP-1, macrophage chemoattractant factor-1; TGF-β, transforming growth factor-β. Modified from Kai et al [29].

Fig. (5)

Effects of non-depressor dose of candesartan (Cand) on the large blood pressure variability-induced hypertensive cardiac remodeling (A), left ventricular (LV) fractional shortening (B), and inflammatory changes (C). SHR, spontaneously hypertensive rat; SAD, bilateral sinoaortic denervation; MCP-1, macrophage chemoattractant factor-1, TGF-β, transforming growth factor-β. Modified from Kudo et al [20]

Fig. (6)

Effects of non-depressor dose of eplerenone (EPL) on the large blood pressure variability-induced hypertensive cardiac remodeling in SHR. A. Pooled data showing the changes in myocyte diameter and %myocardial fibrosis. B. Pooled data showing the changes in braintype natriuretic peptide (BNP) mRNA expression (a) and transforming growth factor-β (TGF-β) mRNA expression (b), and macrophage infiltration (c). SAD, bilateral sino-aortic denervation. Modified from Yasuoka et al [33].

Fig. (7)

Effects of simvastatin (Simva) on the large blood pressure variability-induced RhoA activation (A), Ras activation (B), ERK1/2 phosphorylation (C), and cardiac remodeling (D). SHR, spontaneously hypertensive rat; SAD, bilateral sino-aortic denervation. Modified from Takayama et al [34].

Fig. (8)

Renal cortex damage induced by a combination of hypertension and large blood pressure variability. A. Representative microphotograph of hematoxylin-eosin stained renal cortex section showing focal ischemic sclerotic lesion. B. Representative microphotographs of hematoxylin-eosin stained renal cortex sections showing vascular wall thickening with luminal narrowing (arrow, left panel) and occlusion (arrow head, right panel) of the pre-glomerular arterioles. C. Correlation between the extent of BP variability, standard deviation of mean blood pressure (SD of mBP), and %ischemic sclerotic lesion area. D. Pooled data showing the effects of non-depressor dose of candesartan (Cand) on the ischemic sclerotic lesion area (a) and the number of the arteriolosclerotic lesions (b). SAD, bilateral sino-aortic denervation. Modified from Aoki et al [35].

Fig. (9)

Scheme of proposed molecular mechanism of the large blood pressure (BP) variability-induced aggravation of hypertensive organ damages in the heart and kidney. MR, mineralocorticoid receptor; MCP-1, macrophage chemoattractant factor-1, TGF-β, transforming growth factor-β.