Toru Dejima

Effect of losartan on ambulatory short-term blood pressure variability and cardiovascular remodeling in hypertensive patients on hemodialysis

OBJECTIVE Previous studies have shown increases in ambulatory short-term blood pressure (BP) variability to be related to cardiovascular disease. In this study, we examined whether an angiotensin II type 1 receptor blocker losartan would improve ambulatory short-term BP variability in hypertensive patients on hemodialysis. METHODS Forty hypertensive patients on hemodialysis therapy were randomly assigned to the losartan treatment group (n=20) or the control treatment group (n=20). At baseline and 6 and 12 months after the treatment, 24-h ambulatory BP monitoring was performed. Echocardiography and measurements of brachial-ankle pulse wave velocity (baPWV) and biochemical parameters were also performed before and after therapy. RESULTS After 6- and 12-months of treatment, nighttime short-term BP variability, assessed on the basis of the coefficient of variation of ambulatory BP, was significantly decreased in the losartan group, but remained unchanged in the control group. Compared with the control group, losartan significantly decreased left ventricular mass index (LVMI), baPWV, and the plasma levels of brain natriuretic peptide and advanced glycation end products (AGE). Furthermore, multiple regression analysis showed significant correlations between changes in LVMI and changes in nighttime short-term BP variability, as well as between changes in LVMI and changes in the plasma levels of AGE. CONCLUSION These results suggest that losartan is beneficial for the suppression of pathological cardiovascular remodeling though its inhibitory effect on ambulatory short-term BP variability during nighttime.

Cardiac-Specific Activation of Angiotensin II Type 1 Receptor–Associated Protein Completely Suppresses Cardiac Hypertrophy in Chronic Angiotensin II–Infused Mice

We cloned a novel molecule interacting with angiotensin II type 1 receptor, which we named ATRAP (for angiotensin II type 1 receptor–associated protein). Previous in vitro studies showed that ATRAP significantly promotes constitutive internalization of the angiotensin II type 1 receptor and further attenuates angiotensin II–mediated hypertrophic responses in cardiomyocytes. The present study was designed to investigate the putative functional role of ATRAP in cardiac hypertrophy by angiotensin II infusion in vivo. We first examined the effect of angiotensin II infusion on endogenous ATRAP expression in the heart of C57BL/6J wild-type mice. The angiotensin II treatment promoted cardiac hypertrophy, concomitant with a significant decrease in cardiac ATRAP expression, but without significant change in cardiac angiotensin II type 1 receptor expression. We hypothesized that a downregulation of the cardiac ATRAP to angiotensin II type 1 receptor ratio is involved in the pathogenesis of cardiac hypertrophy. To examine this hypothesis, we next generated transgenic mice expressing ATRAP specifically in cardiomyocytes under control of the &agr;-myosin heavy chain promoter. In cardiac-specific ATRAP transgenic mice, the development of cardiac hypertrophy, activation of p38 mitogen-activated protein kinase, and expression of hypertrophy-related genes in the context of angiotensin II treatment were completely suppressed, in spite of there being no significant difference in blood pressure on radiotelemetry between the transgenic mice and littermate control mice. These results demonstrate that cardiomyocyte-specific overexpression of ATRAP in vivo abolishes the cardiac hypertrophy provoked by chronic angiotensin II infusion, thereby suggesting ATRAP to be a novel therapeutic target in cardiac hypertrophy.

Effects of angiotensin II type 1 receptor blocker on ambulatory blood pressure variability in hypertensive patients with overt diabetic nephropathy.

Previous studies have shown increases in ambulatory short-term blood pressure (BP) variability to be related to cardiovascular disease. In this study, we examined whether the angiotensin II type 1 receptor blocker (ARB) would improve ambulatory short-term BP variability in hypertensive patients with diabetic nephropathy. A total of 30 patients with type II diabetes, along with hypertension and overt nephropathy, were enrolled in this randomized, two-period, crossover trial of 12 weeks of treatment with losartan (50 mg daily) and telmisartan (40 mg daily). At baseline and at the end of each treatment period, 24-h ambulatory BP monitoring with power spectral analysis of heart rate and measurements of proteinuria, estimated glomerular filtration rate and brachial-ankle pulse wave velocity (baPWV) were performed. After 12 weeks of treatment, 24-h, daytime and nighttime short-term BP variability, assessed on the basis of the coefficient of variation of ambulatory BP, was significantly decreased by telmisartan. Both losartan and telmisartan reduced urinary protein excretion and baPWV. However, compared with losartan, telmisartan significantly decreased urinary protein excretion, baPWV and low-frequency (LF)-to-high-frequency (HF) ratio, an index of sympathovagal balance. Multiple regression analysis showed significant correlations between urinary protein excretion and baPWV, 24-h LF-to-HF ratio, nighttime systolic BP and 24-h short-term systolic BP variability. These results suggest that ARB, particularly telmisartan, is effective in reducing proteinuria in hypertensive patients with overt diabetic nephropathy, partly through inhibitory effects on ambulatory short-term BP variability and sympathetic nerve activity, in addition to its longer duration of action on nighttime BP reduction.

Activation of angiotensin II type 1 receptor-associated protein exerts an inhibitory effect on vascular hypertrophy and oxidative stress in angiotensin II-mediated hypertension

AIMS Activation of tissue angiotensin II (Ang II) type 1 receptor (AT1R) plays an important role in the development of vascular remodelling. We have shown that the AT1R-associated protein (ATRAP/Agtrap), a specific binding protein of AT1R, functions as an endogenous inhibitor to prevent pathological activation of the tissue renin-angiotensin system. In this study, we investigated the effects of ATRAP on Ang II-induced vascular remodelling. METHODS AND RESULTS Transgenic (Tg) mice with a pattern of aortic vascular-dominant overexpression of ATRAP were obtained, and Ang II or vehicle was continuously infused into Tg and wild-type (Wt) mice via an osmotic minipump for 14 days. Although blood pressure of Ang II-infused Tg mice was comparable with that of Ang II-infused Wt mice, the Ang II-mediated development of aortic vascular hypertrophy was partially inhibited in Tg mice compared with Wt mice. In addition, Ang II-mediated up-regulation of vascular Nox4 and p22(phox), NADPH oxidase components, and 4-HNE, a marker of reactive oxygen species (ROS) generation, was significantly suppressed in Tg mice, with a concomitant inhibition of activation of aortic vascular p38MAPK and JNK by Ang II. This protection afforded by vascular ATRAP against Ang II-induced activation of NADPH oxidase is supported by in vitro experimental data using adenoviral transfer of recombinant ATRAP. CONCLUSION These results indicate that activation of aortic vascular ATRAP partially inhibits the Nox4/p22(phox)-ROS-p38MAPK/JNK pathway and pathological aortic hypertrophy provoked by Ang II-mediated hypertension, thereby suggesting ATRAP as a novel receptor-binding modulator of vascular pathophysiology.

Intrarenal suppression of angiotensin II type 1 receptor binding molecule in angiotensin II-infused mice

ATRAP [ANG II type 1 receptor (AT1R)-associated protein] is a molecule which directly interacts with AT1R and inhibits AT1R signaling. The aim of this study was to examine the effects of continuous ANG II infusion on the intrarenal expression and distribution of ATRAP and to determine the role of AT1R signaling in mediating these effects. C57BL/6 male mice were subjected to vehicle or ANG II infusions at doses of 200, 1,000, or 2,500 ng·kg(-1)·min(-1) for 14 days. ANG II infusion caused significant suppression of ATRAP expression in the kidney but did not affect ATRAP expression in the testis or liver. Although only the highest ANG II dose (2,500 ng·kg(-1)·min(-1)) provoked renal pathological responses, such as an increase in the mRNA expression of angiotensinogen and the α-subunit of the epithelial sodium channel, ANG II-induced decreases in ATRAP were observed even at the lowest dose (200 ng·kg(-1)·min(-1)), particularly in the outer medulla of the kidney, based on immunohistochemical staining and Western blot analysis. The decrease in renal ATRAP expression by ANG II infusion was prevented by treatment with the AT1R-specific blocker olmesartan. In addition, the ANG II-mediated decrease in renal ATRAP expression through AT1R signaling occurred without an ANG II-induced decrease in plasma membrane AT1R expression in the kidney. On the other hand, a transgenic model increase in renal ATRAP expression beyond baseline was accompanied by a constitutive reduction of renal plasma membrane AT1R expression and by the promotion of renal AT1R internalization as well as the decreased induction of angiotensinogen gene expression in response to ANG II. These results suggest that the plasma membrane AT1R level in the kidney is modulated by intrarenal ATRAP expression under physiological and pathophysiological conditions in vivo.

Blood pressure variability as well as blood pressure level is important for left ventricular hypertrophy and brachial-ankle pulse wave velocity in hypertensives.

Blood pressure (BP) variability is calculated as the standard deviation of ambulatory BP. Blood pressure variability is associated with the cardiovascular morbidity; however whether it is related to target organ damage is controversial. In this study we examined a possible relationship between the BP variability and left ventricular hypertrophy (LVH), and between BP variability and brachial-ankle pulse wave velocity (baPWV). The present study was conducted on 111 consecutive Japanese hypertensive patients who were hospitalized for the educational program in our hospital under stable sodium chloride intake (6 g/day). Blood pressure measurements were at 30-minute intervals all day. In a multivariable analysis adjusted with confounding factor, LVH was associated with 24-hour systolic BP (SBP), 24 hour diastolic BP (DBP), daytime SBP, daytime DBP, nighttime SBP, and nighttime DBP. Additionally, nighttime DBP variability was related to LVH. By the same method, baPWV as a dependent variable was related to 24-hour SBP and nighttime SBP. Furthermore, nighttime SBP variability was concerned with baPWV. The LVH was associated with not only BP level but also with nighttime DBP variability. The baPWV was also related not only to BP level but also to nighttime SBP variability.

Effects of Angiotensin II Type 1 Receptor Blocker on Blood Pressure Variability and Cardiovascular Remodeling in Hypertensive Patients on Chronic Peritoneal Dialysis

Aims: In this study, we examined whether addition of an angiotensin II type 1 receptor blocker (ARB), candesartan or valsartan, to conventional antihypertensive treatment could improve blood pressure (BP) variability in hypertensive patients on peritoneal dialysis. Methods: 45 hypertensive patients on chronic peritoneal dialysis therapy were randomly assigned to the ARB treatment groups either by candesartan (n = 15) or valsartan (n = 15), or the control group (n = 15). At baseline and 6 months after the treatment, 24-hour ambulatory BP monitoring, echocardiography, and measurement of brachial-ankle pulse wave velocity (baPWV) were performed. Results: After the 6 months of treatment, 24-hour ambulatory BP values were similarly decreased in both the control group and ARB groups. However, short-term BP variability assessed on the basis of the standard deviation of 24-hour ambulatory BP was significantly decreased in the ARB groups, but remained unchanged in the control group. Furthermore, parameters of cardiovascular remodeling assessed by natriuretic peptides, echocardiography, and baPWV were significantly improved in the ARB groups but not in the control group. Conclusion: ARB treatment and control antihypertensive treatment similarly controlled 24-hour ambulatory BP values in hypertensive patients on peritoneal dialysis. However, ARB treatment is beneficial for the suppression of pathological cardiovascular remodeling with a decrease in BP variability.

Expression of angiotensin II type 1 receptor-interacting molecule in normal human kidney and IgA nephropathy

The intrarenal renin-angiotensin system plays a crucial role in the regulation of renal circulation and sodium reabsorption through the activation of vascular, glomerular, and tubular angiotensin II type 1 (AT(1)) receptor signaling. We previously cloned a molecule that specifically interacted with the murine AT(1) receptor to inhibit AT(1) receptor signaling, which we named ATRAP (for AT(1) receptor-associated protein). Since murine ATRAP was shown to be highly expressed in the kidney, in the present study we investigated expression and distribution of human ATRAP in normal kidney and renal biopsy specimens from patients with IgA nephropathy. In the normal human kidney, both ATRAP mRNA and protein were widely and abundantly distributed along the renal tubules from Bowmans capsule to the medullary collecting ducts. In all renal tubular epithelial cells, the ATRAP protein colocalized with the AT(1) receptor. In renal biopsy specimens with IgA nephropathy, a significant positive correlation between ATRAP and AT(1) receptor gene expression was observed. There was also a positive relationship between tubulointerstitial ATRAP expression and the estimated glomerular filtration rate in patients with IgA nephropathy. Furthermore, we examined the function of the tubular AT(1) receptor using an immortalized cell line of mouse distal convoluted tubule cells (mDCT) and found that overexpression of ATRAP by adenoviral gene transfer suppressed the angiotensin II-mediated increases in transforming growth factor-β production in mDCT cells. These findings suggest that ATRAP might play a role in balancing the renal renin-angiotensin system synergistically with the AT(1) receptor by counterregulatory effects in IgA nephropathy and propose an antagonistic effect of tubular ATRAP on AT(1) receptor signaling.

The physiology and pathophysiology of a novel angiotensin receptor-binding protein ATRAP/Agtrap.

The Ang II type 1 receptor (AT1R)-associated protein (ATRAP/Agtrap) is a molecule specifically interacting with the carboxyl- terminal domain of AT1R. The results of in vitro studies showed that ATRAP suppresses Ang II-mediated pathological responses in cardiovascular cells by promoting AT1R internalization. With respect to the tissue distribution and regulation of ATRAP expression in vivo, ATRAP is broadly expressed in many tissues as is AT1R. Accumulating evidence indicates that a tissue-specific regulatory balancing of ATRAP and AT1R expression may be involved in the modulation of AT1R signaling at local tissue sites and also in the pathophysiology of hypertension and its associated end-organ injury. Furthermore, the activation of ATRAP in transgenic-models inhibited inflammatory vascular remodeling and cardiac hypertrophy in response to Ang II stimulation. These results suggest the clinical potential benefit of an ATRAP activation strategy in the treatment of hypertension and related organ injury.

Effects of aliskiren-based therapy on ambulatory blood pressure profile, central hemodynamics, and arterial stiffness in nondiabetic mild to moderate hypertensive patients.

J Clin Hypertens (Greenwich). 2012;00:000–000. ©2012 Wiley Periodicals, Inc.