Knee Extensor Weakness Potently Predicts Postoperative Outcomes in Older Gastrointestinal Cancer Patients.

OBJECTIVES: Muscle weakness, assessed by grip strength, has been shown to predict postoperative mortality in older patients with cancer. Because lower extremity muscle strength well reflects physical performance, we examined whether lower knee extension muscle strength predicts postoperative mortality better than grip strength in older patients with gastrointestinal cancer. DESIGN: Prospective, observational study in a single institution. SETTING AND PARTICIPANTS: A total of 813 patients (79.0 ± 4.2 years, 66.5% male) aged 65 years or older with gastrointestinal cancer who underwent preoperative evaluation of grip strength and isometric knee extension muscle strength between April 2012 and April 2019 were included. METHODS: The study participants were prospectively followed up for postoperative mortality. Muscle weakness was defined as the lowest quartile of grip strength or knee extension strength (GS-muscle weakness and KS-muscle weakness, respectively). RESULTS: Among the study participants, 176 patients died during a median follow-up of 716 days. In the Kaplan-Meier analysis, we found that patients with both GS-muscle weakness and KS-muscle weakness had a lower survival rate than those without muscle weakness. As expected, higher clinical stages and abdominal and thoracic surgeries compared with endoscopic surgery were associated with increased all-cause mortality. In addition, we found that KS-muscle weakness, but not GS-muscle weakness, was an independent prognostic factor after adjusting for sex, body mass index, cancer stage, surgical technique, and surgical site in the Cox proportional hazard model. CONCLUSIONS AND IMPLICATIONS: In older patients with gastrointestinal cancer, muscle weakness based on knee extension muscle strength can be a better predictor of postoperative prognosis than muscle weakness based on grip strength.

Assessment of walking disorder in community-dwelling Japanese middle-aged and elderly women using an inertial sensor.

BACKGROUND: Decreased walking speed has been revealed to be related to many negative events. Several researchers support the importance of triceps surae function as a cause of decreased walking speed. The purpose of this study was to investigate the relationship between walking speed and plantar flexor power during the terminal stance of gait in community-dwelling middle-aged and elderly women using an inertial sensor. METHODS: One hundred thirty-six healthy female middle-aged to elderly community-dwelling women were included in this study. We measured two-step score, grip strength, walking speed and accelerometer data from which we estimated ankle power (estimated ankle power) during walking using an inertial sensor. All participants were classified into the four different age strata, fifties (50-59), sixties (60-69), seventies (70-79) and eighties (80-89). The differences in each parameter between the four age groups were compared using repeated analysis of variance and post-hoc Bonferroni corrections for multiple comparisons to establish significance. Multiple regression analysis was carried out using a stepwise method to determine the correlations with comfortable walking speed. Comfortable walking speed was considered a dependent variable. RESULTS: The normalized estimated ankle power of the eighties group was significantly decreased in comparison with seventies age groups and fifties age groups (P < 0.05), but there were no significant differences in normalized estimated ankle power between the sixties and eighties age-groups. The results of stepwise multiple regression analysis revealed that the normalized estimated ankle power, two-step value and body weight were highly-significant partial regression coefficients (adjusted R 2 = 0.57).

Development of a Geriatric Prognostic Scoring System for Predicting Survival After Surgery for Elderly Patients With Gastrointestinal Cancer.

BACKGROUND: The number of elderly patients with gastrointestinal cancer is rising as the population ages. This study aimed to assess the impact of a preoperative geriatric assessment on postoperative survival and to develop a geriatric prognostic scoring system (GPSS) for elderly patients. METHODS: Patients (n = 544) age 75 years or older who had undergone radical surgery for gastrointestinal cancer were recruited for this observational study. Geriatric assessments (GAs) using the Barthel Index, the Mini-Mental State Examination, Instrumental Activities of Daily Living, the Vitality Index, and the Geriatric Depression Score were administered before surgery. Multivariable analysis was performed using a Cox proportional hazard regression model to identify significant prognostic factors. The GPSS was developed using regression coefficients of the multivariable regression to predict overall survival (OS). Thereafter, 165 consecutive patients were prospectively validated to test the authors' model. RESULTS: The independent predictors of OS appeared to be GA as well as age, type of cancer, clinical stage, performance status, and body mass index. The patients were classified into high- and low-risk groups according to the GPSS. The overall 3-year survival was 79% in the low-risk group and 26% in the high-risk group (hazard ratio [HR], 5.69; 95% confidence interval [CI] 4.35-7.42; p < 0.0001). Furthermore, when GPSS was applied to independent cohorts, the patients in the high-risk group showed significantly poorer prognoses than those in the low-risk group (HR, 4.49; 95% CI 2.65-7.60; p < 0.0001). CONCLUSIONS: Geriatric assessments were closely associated with postoperative OS. The GPSS is useful in predicting postoperative prognosis and may help determine treatment strategies for elderly patients with gastrointestinal cancer.

Estimation of the ankle power during the terminal stance of gait using an inertial sensor.

[Purpose] The purpose of this study was to develop an assessment tool that reflects the ankle function during the terminal stance of gait using an inertial sensor. [Participants and Methods] Thirteen healthy males (20 limbs) participated in this study. All the participants were required to perform five straight-line walking trials along a 10-m level walkway. During the terminal stance phase, both the anterior-posterior and vertical accelerations were measured with an inertial sensor mounted on the fibular head. The Pythagorean theorem was used to calculate the acceleration vector. A three-dimensional gait analysis system was used for movement data acquisition. All statistical analyses were performed using IBM SPSS Statistics 24.0 for Windows. [Results] Results were obtained using the following multiple regression equation for the estimation of ankle plantar flexion power: Estimated Ankle Power=-4.689 + 0.269 × vertical acceleration + 0.104 × body weight. [Conclusion] Our novel method for gait analysis using an inertial sensor can assess the ankle power during the terminal stance phase of gait.

Beneficial effect of laughter therapy on physiological and psychological function in elders.

AIM: In the present study we investigated the effect of laughter therapy on physiological and psychological function in older people. DESIGN: An open-label trial. METHODS: Seventeen older people who regularly attended an elderly day care centre were recruited. Stand-up comedy as laughter therapy was performed once a week for 4 weeks. Parameters of physiological and psychological function were evaluated before and after laughter therapy. RESULTS: Laughter therapy intervention resulted in a significant reduction in systolic blood pressure and heart rate, accompanied by a significant increase in plasma concentration of serotonin and a significant decrease in salivary concentration of chromogranin A. Questionnaire surveys of SF-8, GDS-15, and Vitality Index demonstrated alleviation of depression and improvement of sociability and activity in older people. Laughter therapy could be expected to become a practical treatment to improve quality of life of older people in an elderly day care centre.

Risk Evaluation of Postoperative Delirium Using Comprehensive Geriatric Assessment in Elderly Patients with Esophageal Cancer.

BACKGROUND: The number of geriatric patients with esophageal cancer is increasing in step with the aging of the population. Geriatric patients have a higher risk of postoperative complications, including delirium that can cause a fall or impact survival. Therefore, it is very important that we evaluate risks of postoperative complications before surgery. The aim of this study was to predict postoperative delirium in elderly patients. METHODS: We retrospectively reviewed the medical records of 91 patients aged 75 years and over who underwent esophagectomy between January 2006 and December 2014. We investigated the association between postoperative delirium and clinicopathological factors, including comprehensive geriatric assessment (CGA). RESULTS: Postoperative delirium developed in 24 (26 %) patients. Postoperative delirium was significantly associated with low mini-mental state examination (MMSE) and high Geriatric Depression Scale 15 (GDS15), which are components of CGA, and psychiatric disorder (P < 0.0001, P = 0.002, and P = 0.017, respectively). With multiple logistic regression analysis, MMSE (odds ratio [OR], 1.4; 95 % confidence interval [CI], 1.2-1.6; P < 0.0001] and GDS15 (OR, 1.3; 95 % CI, 1.1-1.6; P = 0.004) were independently associated with postoperative delirium. CONCLUSIONS: Preoperative CGA, especially MMSE and GDS15, was useful for predicting postoperative delirium in elderly patients undergoing esophagectomy for esophageal cancer. Intervention by a multidisciplinary team using CGA might help prevent postoperative delirium.

Comprehensive Geriatric Assessment is a useful predictive tool for postoperative delirium after gastrointestinal surgery in old-old adults.

AIM: To determine whether carrying out the Comprehensive Geriatric Assessment before operations would be useful for predicting complications, particularly postoperative delirium (POD), in old-old patients. METHODS: A total of 517 patients aged 75 years and older, who underwent radical surgery for gastrointestinal cancer at Osaka University Hospital, were recruited for this observational study. The Comprehensive Geriatric Assessment components and assessment of performance status were carried out before surgery, and a record of postoperative complications including POD was made prospectively until discharge from hospital. The following morphological and clinical measurements were also obtained from the medical records: age, sex, disease type, previous history, comorbid lifestyle-related diseases, POD, postoperative complications, operative method, duration of operation, hemorrhage volume, blood transfusion volume, method of anesthesia, body mass index and blood tests. RESULTS: POD appeared in 24.0% of the 517 patients who underwent surgery. Barthel Index, Mini-Mental State Examination, instrumental activities of daily living and Geriatric Depression Scale results were associated with the incidence of POD, and the Barthel Index, Mini-Mental State Examination and Instrumental Activities of Daily Living results were extracted as independent factors associated with the development of POD after adjusting for traditional risk factors for postoperative complications and performance status. CONCLUSIONS: The Comprehensive Geriatric Assessment before gastrointestinal surgery can be a useful tool for predicting the development of POD in old-old patients. Geriatr Gerontol Int 2016; 16: 1036-1042.

Oxidized LDL (oxLDL) activates the angiotensin II type 1 receptor by binding to the lectin-like oxLDL receptor.

The angiotensin II type 1 receptor (AT1) is a 7-transmembrane domain GPCR that when activated by its ligand angiotensin II, generates signaling events promoting vascular dysfunction and the development of cardiovascular disease. Here, we show that the single-transmembrane oxidized LDL (oxLDL) receptor (LOX-1) resides in proximity to AT1 on cell-surface membranes and that binding of oxLDL to LOX-1 can allosterically activate AT1-dependent signaling events. oxLDL-induced signaling events in human vascular endothelial cells were abolished by knockdown of AT1 and inhibited by AT1 blockade (ARB). oxLDL increased cytosolic G protein by 350% in Chinese hamster ovary (CHO) cells with genetically induced expression of AT1 and LOX-1, whereas little increase was observed in CHO cells expressing only LOX-1. Immunoprecipitation and in situ proximity ligation assay (PLA) assays in CHO cells revealed the presence of cell-surface complexes involving LOX-1 and AT1. Chimeric analysis showed that oxLDL-induced AT1 signaling events are mediated via interactions between the intracellular domain of LOX-1 and AT1 that activate AT1. oxLDL-induced impairment of endothelium-dependent vascular relaxation of vascular ring from mouse thoracic aorta was abolished by ARB or genetic deletion of AT1. These findings reveal a novel pathway for AT1 activation and suggest a new mechanism whereby oxLDL may be promoting risk for cardiovascular disease.

-374 T/A polymorphism in RAGE gene is associated with onset of diabetes mellitus, atherosclerosis, and renal dysfunction in patients with hypertension.

Receptor of advanced glycation end products (RAGE) is reportedly linked with chronic inflammatory diseases due to aging or diabetes. The aim of this study was to show how -374 T/A RAGE has an impact on systemic vascular damage and renal function. The study subjects were a total of 468 essential hypertension patients from the Non-Invasive Atherosclerotic Evaluation in Hypertension (NOAH) study cohort. We prospectively examined the association of -374 T/A RAGE with their prognoses and investigated the correlation between -374 T/A RAGE and multiple clinical parameters. Kaplan-Meier analysis did not show a significant association of -374 T/A RAGE with total mortality or the prevalence of cardiovascular events. Carriers of the A allele showed a significantly higher prevalence of diabetes mellitus (DM) and lower estimated glomerular filtration rate (eGFR) than subjects without this allele. In subjects with DM, carriers of the A allele showed a significantly lower eGFR. These significant correlations were only seen in male subjects. Carriers of the A allele of -374 T/A RAGE show an independent risk of atherosclerosis and reduced renal function in male hypertensive patients with DM.

Cut-off value of brachial-ankle pulse wave velocity to predict cardiovascular disease in hypertensive patients: a cohort study.

AIM: Arterial stiffness has been reported to correlate with cardiovascular disease (CVD). Brachial-ankle pulse wave velocity (baPWV) is easy to measure and has been used as a marker to evaluate arterial stiffness. The objective of the present study was to determine the cut-off value of baPWV for predicting cardiovascular prognosis in a prospective cohort study. METHODS: Four hundred forty patients with essential hypertension were analyzed in study 1 with a mean follow-up of 6.3±0.1 years. Four hundred patients from study 1 who did not have a past history of CVD and/or stroke were analyzed in study 2 with a mean follow-up of 6.4±0.1 years. Stroke, CVD, and death were the primary endpoints. RESULTS: Receiver operating characteristic (ROC) curve analysis revealed that 1750.0 cm/sec is an appropriate cut-off value for baPWV to predict the onset of stroke, CVD, stroke+CVD, and total mortality (area under curve: 0.576-0.719). A baPWV higher than 1750.0 may also be a significant and independent risk factor for the onset of CVD+stroke (relative risk: 2.048 (1.176-3.616), p= 0.0113 in study 1; relative risk: 1.920 (1.028-3.634), p=0.0408 in study 2). CONCLUSIONS: The present study indicates that 1750.0 cm/sec could be a useful cut-off value for baPWV to predict cardiovascular prognosis.

Relationship between renal hemodynamic status and aging in patients without diabetes evaluated by renal Doppler ultrasonography.

BACKGROUND: Aging is well known as one of the major causes of a reduced glomerular filtration rate (GFR). The resistive index (RI) measured by renal Doppler ultrasonography (RDU) is thought to be a good indicator of renal vascular resistance induced by arteriosclerosis. In this study, we investigated whether RI could be used to evaluate the pathogenesis of renal damage or the mechanisms of reduction of renal function by aging. METHODS: We investigated the correlation between RI and multiple clinical parameters and the influence of aging on the renal hemodynamic status of 194 in-patients (mean age 66.2 years) who underwent RDU at our hospital between February 2009 and July 2010. RESULTS: RI was significantly correlated with the age, estimated GFR (eGFR), diastolic blood pressure, pulse pressure, and degree of albuminuria. Subjects aged ≥75 years showed a significantly higher correlation coefficient between eGFR and RI. RI showed a stronger correlation with age in subjects aged ≥75 years compared to eGFR. CONCLUSION: The present study showed that renal vascular resistance and intra-renal arteriosclerosis had a greater impact on renal function in older than younger subjects, reflecting the possible mechanisms of renal function reduction due to aging.

The combination of chronic kidney disease and increased arterial stiffness is a predictor for stroke and cardiovascular disease in hypertensive patients.

To clarify the clinical utility of pulse wave velocity (PWV) and chronic kidney disease (CKD) in hypertension, we analyzed the prognostic impact of PWV and CKD on cerebrocardiovascular disease in hypertensive patients. This study consisted of 531 patients with essential hypertension (male/female=292/239, mean age=61.7±12.3, mean follow-up=7.0±3.0 years) and was performed between January 1998 and June 2004. We used questionnaires to assess stroke (n=57), cardiovascular diseases (CVDs; myocardial infarction, angina and congestive heart failure; n=44) and death (n=53) as primary end points. At baseline, we evaluated the carotid-femoral PWV (9.1±1.8 m s(-1)), the glomerular filtration rate and urinary protein excretions. We divided these subjects into those in the highest quartile of PWV and other subjects and into CKD (n=149) and non-CKD (n=458). We evaluated the prognostic influences of PWV and CKD with Kaplan-Meier analysis and Cox's proportional hazard model. PWV in CKD (9.6±1.9 m s(-1)) was higher than in non-CKD (8.8±1.6 m s(-1); P<0.0001), and creatinine was slightly decreased in the highest PWV group (1.09±0.35 mg dl(-1), P<0.0001). On the basis of Kaplan-Meier analysis, the highest PWV group (PWV>10.1 m s(-1); P=0.0003) and the CKD group (P=0.0005) showed significantly higher proportions of stroke and CVD events. In addition, the highest PWV group showed the highest percentage of stroke (P=0.0007), and the CKD group showed the highest proportion of CVD (P<00001). High PWV and CKD were independent predictors for stroke and CVD (P=0.0332) by Cox's proportional hazard model. These data suggest that increased aortic stiffness and CKD may be predictors for stroke and cardiovascular events in hypertensive patients.

Klotho protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway.

AIM: Mice that carry the Klotho mutation (KL(-) (/) (-) ) manifest diverse age-related disorders similar to those observed in humans. Thus, the Klotho protein might function as an anti-aging hormone in mammals. Recently, we reported that Klotho recombinant protein attenuated apoptosis and cellular senescence in endothelial cells, but the mechanism remained unclear. Here, we designed an in vitro study to test whether inhibitors of extracellular signal-regulated kinase and mitogen-activated kinase kinase could affect Klotho regulation of apoptosis and cellular senescence. METHODS: Cellular senescence was investigated in human umbilical vein endothelial cells treated with or without Klotho recombinant protein, and with or without inhibitors of mitogen-activated kinases. Senescence was quantified by staining with senescence-associated ß-galactosidase and by evaluating western blots probed for phosphorylation of mitogen-activated kinases. Apoptosis was assayed on western probed for p53, p21, and caspase-3 and -9. RESULTS: The Klotho recombinant protein induced transient phosphorylation of mitogen-activated kinases within a few minutes. Application of inhibitors of mitogen-activated kinases attenuated the ability of Klotho to interfere with apoptosis and senescence in endothelial cells. CONCLUSION: This study demonstrated that Klotho attenuated cellular apoptosis and senescence in vascular cells via mitogen-activated kinase kinase and extracellular signal-regulated kinase pathways.

Angiotensin-converting enzyme single nucleotide polymorphism is a genetic risk factor for cardiovascular disease: a cohort study of hypertensive patients.

The renin-angiotensin system (RAS) adversely affects stroke and cardiovascular disease; polymorphisms in genes involved in this system are associated with cardiovascular disease. The aim of the present study was to confirm the genetic risk of these polymorphisms for stroke and cardiovascular events in a cohort study of 515 hypertensive patients in Japan (follow-up period 90.6±30.2 months). The insertion/deletion (I/D) polymorphism of the gene encoding angiotensin-converting enzyme (ACE), the M235T amino acid change in angiotensinogen, and the A1166C polymorphism in angiotensin II type 1 receptor were determined by TaqMan PCR. In Kaplan-Meier analyses, the ACE I/D polymorphism was a risk factor for cerebro-cardiovascular events, especially cardiovascular events (P<0.0001), and the M235T mutation was a risk factor for cardiovascular events (P<0.0105). The cumulative rates of cerebro-cardiovascular end points for the ACE polymorphism were 10.6, 16.4 and 42.2% for the II (n=207), ID (n=244) and DD (n=64) genotype carriers, respectively (P<0.0001). Cox's proportional hazard models revealed that the ACE DD genotype was a risk factor for cerebro-cardiovascular and cardiovascular events (after adjusting for common risk factors), anti-hypertensive treatment and RAS inhibition (P<0.0001). Moreover, after adjustment for the common risk factors left ventricular hypertrophy and previous myocardial infarction/stroke, these phenomena were preserved. Thus, the DD genotype of ACE may be a genetic risk factor for cerebro-cardiovascular disease, especially cardiovascular events, in hypertensive patients in Japan.

ß-Adrenergic receptor gene polymorphism is a genetic risk factor for cardiovascular disease: a cohort study with hypertensive patients.

Single-nucleotide polymorphisms (SNPs) of the ß-adrenergic receptor (ßADR) subtypes are related to hypertension and obesity. This hospital-based cohort study with hypertensive patients evaluated five ßADR SNPs in association with cardiovascular events. The cohort included 357 hypertensive patients (male = 181; mean age = 61.5 ± 11.8 years) seen between January 1998 and June 2004. The SNPs (Ser49Gly and Arg389Gly for ß(1)ADR; Gly16Arg and Glu27Gln for ß(2)ADR; Trp64Arg for ß(3)ADR) were identified by PCR. We used Kaplan-Meier curves to assess the prognostic effect of these SNPs on cardiovascular disease (CVD). The SNP frequencies were Ser/Ser:Ser/Gly:Gly/Gly = 243:104:10; Arg/Arg:Arg/Gly:Gly/Gly = 256:95:6; Gly/Gly:Gly/Arg:Arg/Arg = 71:201:85; Gln/Gln:Glu/Gln = 308:49; and Trp/Trp:Trp/Arg:Arg/Arg = 265:89:3. A total of 17 stroke and 15 coronary artery disease cases were recorded. By Kaplan-Meier analysis, the Ser/Ser SNP in Ser49Gly (P = 0.0398), the Glu/Gln SNP in Glu27Gln (P = 0.0390) and the Trp/Trp SNP in Trp64Arg (P = 0.0132) were associated with lower event-free CVD survival (log-rank, Mantel-Cox model). A Cox proportional hazards model revealed that only the Trp/Trp SNP (P = 0.0321) and age (P = 0.0186) were independently related to lower event-free survival for CVD, adjusted for gender, diabetes, dyslipidemia, blood pressure, body mass index, medication and hypertensive complications. Combination Kaplan-Meier analysis of these three positive SNPs indicated a higher frequency of CVD among patients with the combination of Ser/Ser in Ser49Gly of ß(1), Glu/Gln in Glu27Gln of ß(2) and Trp/Trp in Trp64Arg of ß(3) (P = 0.0209). These three SNPs, especially the Trp64Arg SNP of ß(3)ADR, might be risk factors for CVD in hypertensive patients.

Strong suppression of the renin-angiotensin system has a renal-protective effect in hypertensive patients: high-dose ARB with ACE inhibitor (Hawaii) study.

The principal means for reducing proteinuria in patients with chronic kidney disease are strong blockade of the renin-angiotensin system and strict regulation of blood pressure (BP). This study compared the efficacy of the maximum permissible doses of two common angiotensin receptor blockers (ARBs), namely valsartan (maximum dose=160 mg per day) and olmesartan (maximum dose=40 mg per day). We also investigated whether a high-dose ARB or the combination of an angiotensin-converting enzyme inhibitor with a high-dose ARB would be more renal protective. We recruited 87 poorly controlled hypertensive patients. In the first study, 50 patients without proteinuria were switched from valsartan (160 mg per day) to olmesartan (40 mg per day) for 4 months. In the second study, 37 patients with proteinuria were randomized to either switch from valsartan 160 mg per day to 40 mg per day olmesartan (n=19; Olm-G) or addition of 2.5-10 mg per day imidapril (stepped up by 2.5 mg per month) to valsartan at 160 mg per day (n=18; Imi-G). After 4 months, the BP level decreased (first study) from 157/88 mm Hg to 145/82 mm Hg (P<0.001) and (second study) from 149/86 mm Hg to 135/77 mm Hg and 145/82 mm Hg for Olm-G and Imi-G, respectively. Furthermore, in the second study, urinary protein/creatinine excretion was reduced from 2.0±1.8 g g⁻¹ to 0.8±0.8 g g⁻¹ (P=0.0242) in Olm-G and from 1.4±1.3 g g⁻¹ to 0.9±1.0 g g⁻¹ (P=0.0398) in Imi-G. The significance persisted after adjustment for BP or other risk factors. Our results suggested that the maximum dose of olmesartan was more effective than that of valsartan and comparable with the combination of valsartan and imidapril for reducing BP and proteinuria in poorly controlled hypertensive patients.

Loss of ACE2 accelerates time-dependent glomerular and tubulointerstitial damage in streptozotocin-induced diabetic mice.

As angiotensin-converting enzyme-2 (ACE2) was identified as a negative regulator of the renin-angiotensin system, there have been many reports concerning its role in several tissues, including the kidney. However, the role of ACE2 during the development of diabetic nephropathy remains undetermined, as previous reports did not necessarily support a protective role against renal injury. Thus, we performed detailed observations of kidneys in ACE2-knockout (ACE2-KO) mice at early (4 weeks) and advanced (18 weeks) stages of diabetes. ACE2-KO and wild-type C57BL/6 mice were rendered diabetic by intraperitoneal injection of streptozotocin. Diabetic ACE2-KO mice showed earlier onset and more severe progression of albuminuria than those did wild-type mice. The elevation of serum creatinine and urea nitrogen levels at 18 weeks of diabetes was more prominent in ACE2-KO mice. Periodic acid-Schiff-stained cross-section of diabetic ACE2-KO mice showed a more severe time-dependent increase in glomerular/tubulointerstitial damage than did that of wild-type mice, confirmed by the immunostaining of alpha-smooth muscle actin, collagen IV and F4-80 antigen. Glomeruli of diabetic ACE2-KO mice showed earlier and more severe decrease in the expression of nephrin, whose degradation is involved in the onset of albuminuria, and more potent increase of vascular endothelial growth factor expression. In addition, treatment with AT1 receptor blocker olmesartan significantly, but not totally, ameliorated the functional and morphological deterioration of diabetic nephropathy in ACE2-KO mice. These results suggest that ACE2 might continuously protect from both glomerular and tubulointerstitial injury during the development of diabetic nephropathy. The renal-protective effect of ACE2 might involve more than just suppressing angiotensin II-mediated AT1 receptor signaling.

Effects of hydroxyhydroquinone-reduced coffee on vasoreactivity and blood pressure.

Recent studies suggest that chlorogenic acids, which are the main components of the polyphenol class in coffee, decrease blood pressure, and that hydroxyhydroquinone (HHQ), which is generated by roasting coffee beans, inhibits the antihypertensive effect of chlorogenic acids in brewed coffee. Here, we examined the vasoreactivity and antihypertensive effects of HHQ-reduced coffee in mild hypertension. The study design was a double blind, randomized, placebo-controlled intervention study, with a 4-week run-in period, followed by an 8-week test beverage ingestion period. The subjects were Japanese men and women with mild hypertension and vascular failure, who were not taking any antihypertensive drugs. During the test beverage ingestion period, the subjects ingested either active or placebo HHQ-reduced coffee (chlorogenic acids per 184 ml of coffee: active, 300 mg; and placebo, 0 mg) daily. Subjects were randomly divided into two groups: active group (n=9) and placebo group (n=12). In the active beverage group, endothelium-dependent, flow-mediated vasodilation impairment was significantly ameliorated and systolic blood pressure was significantly decreased from the baseline, but not in the placebo group. There were no test beverage consumption-related changes in other parameters that may influence blood pressure, such as pulse, cardiac output, body weight or 24-h urine volume. Ingestion of the active beverage significantly decreased urinary isoprostane levels, suggesting a reduced oxidative stress. These findings indicate that HHQ-reduced coffee decreased blood pressure in subjects with mild hypertension. The decreased blood pressure was associated with improved vascular endothelial function.

Klotho suppresses TNF-alpha-induced expression of adhesion molecules in the endothelium and attenuates NF-kappaB activation.

Klotho is a senescence suppressor protein that, when overexpressed, extends the lifespan of mice. Klotho-disrupted mice exhibit atherosclerosis and endothelial dysfunction, which led us to investigate the effect of the Klotho protein on vascular inflammation, particularly adhesion molecule expression. In this study, human umbilical vein endothelial cells (HUVECs) were preincubated with Klotho protein and then exposed to tumor necrosis factor-alpha (TNF-alpha) or vehicle. Reverse transcription-PCR and Western blot analyses revealed that Klotho suppressed TNF-alpha-induced expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). NF-kappaB activation, IkappaB phosphorylation induced by TNF-alpha were also attenuated by Klotho protein administration. The inhibition of eNOS phosphorylation by TNF-alpha was reversed by Klotho. Furthermore, Klotho inhibited TNF-alpha-induced monocyte adhesion to HUVECs and suppressed adhesion molecule expression in an organ culture of the rat aorta. These results suggest that Klotho suppresses TNF-alpha-induced expression of adhesion molecules and NF-kappaB activation. Klotho may have a role in the modulation of endothelial inflammation.