Avshalom Leibowitz

Protective role of vascular smooth muscle cell PPARγ in angiotensin II-induced vascular disease

AIMS Vascular peroxisome proliferator-activated receptor γ (PPARγ) activation improves vascular remodelling and endothelial function in hypertensive rodents. The goal of this study was to determine that vascular smooth muscle cell (VSMC) PPARγ exerts a vascular protective role beyond its metabolic effects. METHODS AND RESULTS We generated a model of adult inducible VSMC-specific Pparγ inactivation to test the hypothesis that PPARγ counteracts angiotensin (Ang) II-induced vascular remodelling and endothelial dysfunction. Inducible VSMC Pparγ knockout mice were generated by crossing Pparγ floxed mice with mice expressing a tamoxifen-inducible Cre recombinase Smooth muscle (Sm) myosin heavy chain promoter control. Eight-to-ten-week-old SmPparγ(-/-) and control mice were infused with a nonpressor dose of Ang II for 7 days. Blood pressure was unaffected. Mesenteric arteries showed eutrophic remodelling in Ang II-infused control mice and hypertrophic remodelling in Ang II-infused SmPparγ(-/-) mice. Endothelium-dependent relaxation to acetylcholine was reduced in SmPparγ(-/-) mice and further impaired by Ang II infusion, and was unaffected by an inhibitor of NO synthase, suggesting a defect of NO-mediated relaxation. SmPparγ deletion increased the sensitivity to Ang II-induced contraction. SmPparγ(-/-) mice exhibited enhanced Ang II-induced vascular NADPH oxidase activity and adhesion molecule ICAM-1 and chemokine monocyte chemotactic protein-1 expression. The antioxidant Superoxide dismutase 3 expression was decreased by SmPparγ deletion. Ang II infusion increased the expression of CD3 T-cell co-receptor chain δ and decreased Adiponectin in perivascular adipose tissue of SmPparγ(-/-) mice. CONCLUSION Inducible Pparγ inactivation in VSMCs exacerbated Ang II-induced vascular remodelling and endothelial dysfunction via enhanced vascular oxidative stress and inflammation, revealing the protective role of VSMC PPARγ in angiotensin II-induced vascular injury.

The role of melatonin in the pathogenesis of hypertension in rats with metabolic syndrome.

BACKGROUND Melatonin, the primary hormone of the pineal gland, is a known modulator of various physiological processes. The aim of this study was to evaluate the role of melatonin in the pathogenesis of hypertension in rats with metabolic syndrome and to assess whether melatonin supplementation prevents the development of hypertension in this model. METHODS Twenty male Sprague-Dawley (SD) rats were fed either a high fructose diet (n = 10) or a regular diet (control; n = 10) for 5 weeks. Urinary excretion of 6-hydroxymelatoninsulfate (a metabolite of melatonin) was measured at the beginning and the end of the study. An additional 20 SD rats were fed with the same diets but with a supplementation of melatonin (30 mg/kg/day) in their drinking water. Blood pressure (BP) was measured every week. RESULTS BP increased significantly in rats fed with a high fructose diet and remained unchanged in the control group. The BP rise was associated with a significant decrease in melatonin secretion during sleep. Melatonin supplementation prevented the BP rise in fructose fed rats. BP increased by 14.6 +/- 1.0 mm Hg in the fructose fed rats, whereas it increased by only 3 +/- 2.6 mm Hg in rats fed with fructose and melatonin (P < 0.001 between groups). CONCLUSIONS Melatonin secretion decreased in fructose fed rats that developed hypertension. Administration of melatonin blunted this BP rise. These data suggested that melatonin plays a role in the pathogenesis of hypertension in rats with metabolic syndrome.

Melatonin prevents kidney injury in a high salt diet-induced hypertension model by decreasing oxidative stress

Melatonin, a potent antioxidant molecule, plays a role in blood pressure regulation. We hypothesized that melatonin may generate a protective effect in a high salt diet (HSD) rodent model mediated by decreasing renal oxidative stress. Dahl salt‐sensitive rats were divided into three groups according to diet: normal chow (control); HSD; HSD with melatonin [30/mg/kg/day]) placed in their water (HSD + Mel) over an 8‐wk period. Blood pressure was measured by the tail cuff method. Kidney injury was evaluated by 24 H urine protein excretion. Glomerular injury index (GII) (fibrotic glomeruli/100 glomeruli) was evaluated from a Massons trichrome‐stained section. Kidney oxidative stress was determined by superoxide production via dihydroethidium staining. Expression of oxidative stress‐related genes was measured by reverse transcriptase‐qPCR. Melatonin had no effect on blood pressure increase induced by HSD and attenuated proteinuria induced by HSD (HSD – 50.7 ± 12, HSD + Mel – 22.3 ± 4.3, controls – 6.5 ± 1.0 gram protein/gram creatinine, P < 0.001). HSD‐induced glomerular damage was significantly diminished by melatonin (GII in HSD – 24 ± 6, HSD + Mel – 3.6 ± 0.8, controls – 0.8 ± 0.5, P < 0.05). Superoxide production was significantly higher in kidneys of HSD fed rats than the controls (99 ± 9 versus 60 ± 7 relative fluorescent units (RFU)/μm2, respectively, P < 0.05). Melatonin also decreased superoxide production (74 ± 5 RFU/μm2, P < 0.05). The expression of kidney inducible nitric oxide synthase and p67phox mRNA was significantly higher in HSD than in the controls and HSD + Mel rats. Treatment with melatonin eliminated the deleterious effect of HSD in the kidneys of Dahl salt‐sensitive rats. The beneficial effect of melatonin is not mediated by lowering blood pressure but by a direct antioxidative effect.

Orthostatic Hypotension Is Associated With Nocturnal Change in Systolic Blood Pressure

BACKGROUND The circadian pattern of blood pressure (BP) has yet to be defined among individuals with orthostatic hypotension (OH). The objective of this study was to evaluate whether OH is associated with nocturnal change in systolic BP. METHODS In a prospective study, we evaluated patients who were referred for 24-h ambulatory blood pressure monitoring (ABPM). All subjects underwent orthostatic BP testing before recording their respective 24-h ABPM. RESULTS The study includes 185 subjects, 114 males, mean age 58 ± 18 years (range 19-89). Participants were classified, based on pattern of systolic BP changes at night, as dippers (greater than 10% decrease; n = 74), nondippers (0-10% decrease; n = 77), and reverse-dippers (increase; n = 34). Nineteen patients (10.3%) had OH. Almost all participants with OH (95%) had an abnormal diurnal BP pattern, and most of them (58%) were reverse-dippers, whereas only 56% of the participants without OH had an abnormal diurnal BP variation, and only 14% were reverse-dippers (P < 0.001). Systolic BP decreased with upright posture by 12 and 2 mm Hg in the reverse-dippers and the nondippers, respectively, and increased by 2 mm Hg in the dippers (P < 0.001). Postural changes in systolic BP were inversely related to the changes between day and night BP readings(r = -0.43; P < 0.01). In a multivariate linear regression analysis, orthostatic BP change, use of ≥2 antihypertensive drugs and female sex were related to nocturnal BP changes. CONCLUSIONS The decrease in BP during upright posture may be a marker of nondipping or reverse-dipping pattern of diurnal BP.

High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aβ deposition in an Alzheimer mouse model

There is growing evidence of the involvement of advanced glycation end products (AGEs) in the pathogenesis of neurodegenerative processes including Alzheimers disease (AD) and their function as a seed for the aggregation of Aβ, a hallmark feature of AD. AGEs are formed endogenously and exogenously during heating and irradiation of foods. We here examined the effect of a diet high in AGEs in the context of an irradiated diet on memory, insoluble Aβ42, AGEs levels in hippocampus, on expression of the receptor for AGEs (RAGE), and on oxidative stress in the vasculature. We found that AD‐like model mice on high‐AGE diet due to irradiation had significantly poorer memory, higher hippocampal levels of insoluble Aβ42 and AGEs as well as higher levels of oxidative stress on vascular walls, compared to littermates fed an isocaloric diet. These differences were not due to weight gain. The data were further supported by the overexpression of RAGE, which binds to Aβ42 and regulates its transport across the blood–brain barrier, suggesting a mediating pathway. Because exposure to AGEs can be diminished, these insights provide an important simple noninvasive potential therapeutic strategy for alleviating a major lifestyle‐linked disease epidemic.

Diabetes mellitus with normal renal function is associated with anaemia.

Anaemia is a common complication of diabetes mellitus (DM), usually related to renal failure. There is scarce information as to the levels of haemoglobin (Hb) and the rate of anaemia in diabetic patients with normal renal function. We, therefore, evaluated haemoglobin levels and the rate of anaemia in diabetic subjects with normal renal functions [estimated glomerular filtration rate (eGFR) > 60 mL/min].

The association between normal-range admission potassium levels in Israeli patients with acute coronary syndrome and early and late outcomes

AbstractAbnormal serum potassium levels are associated with an increased risk of ventricular arrhythmias and mortality in patients with acute myocardial infarction (AMI). The aim of the present study was to evaluate whether different levels of serum potassium, within the normal range, are associated with worse outcomes. The present study comprised 1277 patients with AMI and normal-range admission potassium levels (3.5–5.2 mEq/L), who were enrolled and prospectively followed up in the Acute Coronary Syndrome Israeli Survey between 2010 and 2013. Patients were divided into 4 quartiles based on admission potassium levels; “normal-low” (K ≥ 3.5 and K ⩽ 3.9), “normal-moderate” (K > 3.9 and K ⩽ 4.18), “normal-high” (K > 4.18 and K ⩽ 4.45), and “normal-very high” (K > 4.45 and K ⩽ 5.2). We analyzed the association between admission serum potassium levels and 7 days in-hospital complication rates, and 30-day and 1-year all-cause mortality rates. Patients with “normal-very high” potassium displayed increased frequency of baseline clinical risk factors and experienced a higher rate of acute kidney injury during hospitalization compared with the “normal-low” group (7.7% vs 2.4%; P = 0.002). However, the rate of in-hospital ventricular arrhythmias was similar across the range of admission potassium levels (overall P = 0.26), Multivariate analysis showed that compared with “low-normal” potassium values, patients with “normal-very high” potassium levels experienced increased risk for 30-days (adjusted hazard ratio 2.88, 95% confidence interval 1.05–7.87, P = 0.039) and 1-year all-cause mortality (adjusted hazard ratio 1.98, 95% confidence interval 1.05–3.75, P = 0.034). In patients admitted with AMI, admission serum potassium levels of 4.45 to 5.2 mEq/L are not associated with in-hospital ventricular arrhythmias, but are associated with increased short and long-term mortality.

Serum potassium levels predict blood pressure response to aldosterone antagonists in resistant hypertension.

The objective of this study was to identify factors associated with the blood pressure (BP) response to spironolactone—aldosterone receptor antagonist as an add-on therapy in patients with resistant hypertension (HTN). We retrospectively reviewed the data of subjects with resistant HTN who were treated with add-on spironolactone in a large HTN clinic. A paired Student’s t-test was used to assess the differences between the BP values before and during spironolactone administration, and multivariate analysis was used to assess the predictors of a satisfactory BP response (a decrease in systolic BP >10%). We analyzed the data of 48 hypertensive participants. The add-on spironolactone therapy had a significant BP-lowering effect in both systolic and diastolic BP values (P<0.01 for both). Baseline serum potassium levels of <4.5 mEq l−1 were associated with a satisfactory BP response (P<0.01). Furthermore, every decrement of 1 mEq l−1 of serum potassium was independently associated with a fivefold higher rate of achieving a satisfactory BP response to spironolactone therapy (P=0.024). Additional factors independently associated with an improved systolic BP response were old age (P=0.033), body mass index (P=0.033) and high baseline systolic BP (P=0.004). Our results support the use of add-on spironolactone therapy in patients with resistant HTN who are elderly and obese and have high systolic BP and serum potassium levels <4.5 mEq l−1.

Blunted Blood Pressure Response and Elevated Plasma Adiponectin Levels in Female Sprague Dawley Rats

BACKGROUND Premenopausal women have lower blood pressure (BP) levels than men of similar age. Adiponectin has been shown to play a role in the pathogenesis of hypertension. The aim of the present study was to compare the effect of various stress stimuli on BP and plasma adiponectin levels in male and female Sprague Dawley (SD) rats. METHODS In three experimental models of hypertension, fructose-enriched diet, high salt diet, or L-NAME, were administered for up to 4 weeks. BP, metabolic parameters, and plasma adiponectin were measured at baseline and during the studies. The fructose diet protocol was repeated in female rats for 2 weeks with the addition of testosterone injections or vehicle. RESULTS Females, in contrast to males, did not develop fructose-induced hypertension. Total plasma triglycerides (TGs) were half in females at baseline (P < 0.001) and a third at 4 weeks (P < 0.05). Plasma insulin levels were 23% lower in females than in males at baseline (P < 0.05) and 42% lower after 4 weeks of fructose-enriched diet (P = 0.001). Plasma adiponectin levels were 65% higher in females than in males at baseline (P = 0.001) and 45% higher after 4 weeks of fructose-enriched diet (P < 0.05). Furthermore, female rats showed blunted BP response and elevated plasma adiponectin in the salt-induced and L-NAME-induced hypertension models. Testosterone injection to female rats reduced plasma adiponectin and reversed the blunted BP response. CONCLUSIONS Elevated plasma adiponectin levels, perhaps due to lack of suppression by testosterone, are associated with a blunting of BP response in female compared to male SD rats.

Exaggerated Blood Pressure Response to Exercise Is Not Associated With Masked Hypertension in Patients With High Normal Blood Pressure Levels

The association between exaggerated blood pressure (BP) response to exercise (ExBPR) and “masked hypertension” is unclear. Medical records of patients with high‐normal BP who were evaluated in the Chaim Sheba Screening Institute Ramat Gan, Israel, during the years 2002–2007 and referred for 24‐hour ambulatory BP monitoring (ABPM) and exercise test were reviewed. Data on exercise tests performed in the preceding 5 years were retrieved. Reproducible ExBPR was defined when it was recorded at least twice. BP levels on 24‐hour ABPM were compared between patients with a normal BP response and those with an ExBPR (systolic BP ≥200 mm Hg). Sixty‐nine normotensive patients with high normal BP levels were identified. ExBPR was recorded in 43 patients and was reproducible in 28. BP levels on 24‐hour ABPM were similar in patients with and without ExBPR. In patients with high‐normal BP levels, ExBPR is not associated with masked hypertension.