Circulating Cytokine Levels and Cardiovascular Disease Risk Profile in Young Adult Offspring of Women with Type 1 Diabetes.

INTRODUCTION: Cytokines are key players in the development of both type 1 diabetes (T1D) and cardiovascular disease (CVD). Offspring of women with T1D are known to have an increased risk of early-onset CVD. We studied whether an increased risk of CVD can be observed in the cytokine profile among young adult offspring of women with T1D. METHODS: This cross-sectional case-control study included 67 offspring of women with T1D (cases) and 79 control participants (controls). At an age of 18-23 years, they participated in a clinical assessment including laboratory tests and questionnaires. Cytokine levels were analyzed from venous blood samples after 10 h fasting using Quansys biosciences Q-Plex™ High Sensitivity Human Cytokine Array. RESULTS: Circulating cytokine levels were in general similar between the groups. The circulating levels of interferon-γ (1.78 [IQR 1.20, 2.36] pg/mL versus 2.57 [IQR 1.50, 3.89] pg/mL) (p = 0.006) were lower in cases than controls. CONCLUSION: The findings did not support our hypothesis that serum cytokine profile, determined in early adulthood, was associated with a more adverse CVD risk profile in offspring of women with T1D. Further studies are warranted to find out whether cytokines could serve as early biomarkers of CVD development or whether changes in the cytokine levels over years could be used to monitor CVD progression in offspring of women with T1D.

High blood pressure-lowering and vasoprotective effects of milk products in experimental hypertension.

Milk casein-derived angiotensin-converting enzyme (ACE)-inhibitory tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro) have been shown to have antihypertensive effects in human subjects and to attenuate the development of hypertension in experimental models. The aim of the present study was to investigate the effect of a fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro and plant sterols on already established hypertension, endothelial dysfunction and aortic gene expression. Male spontaneously hypertensive rats (SHR) with baseline systolic blood pressure (SBP) of 195 mmHg were given either active milk (tripeptides and plant sterols), milk or water ad libitum for 6 weeks. SBP was measured weekly by the tail-cuff method. The endothelial function of mesenteric arteries was investigated at the end of the study. Aortas were collected for DNA microarray study (Affymetrix Rat Gene 1.0 ST Array). The main finding was that active milk decreased SBP by 16 mmHg compared with water (178 (SEM 3) v. 195 (SEM 3) mmHg; P < 0.001). Milk also had an antihypertensive effect. Active milk improved mesenteric artery endothelial dysfunction by NO-dependent and endothelium-derived hyperpolarising factor-dependent mechanisms. Treatment with active milk caused mild changes in aortic gene expression; twenty-seven genes were up-regulated and eighty-two down-regulated. Using the criteria for fold change (fc) < 0.833 or > 1.2 and P < 0.05, the most affected (down-regulated) signalling pathways were hedgehog, chemokine and leucocyte transendothelial migration pathways. ACE expression was also slightly decreased (fc 0.86; P = 0.047). In conclusion, long-term treatment with fermented milk enriched with tripeptides and plant sterols decreases SBP, improves endothelial dysfunction and affects signalling pathways related to inflammatory responses in SHR.

Ile-Pro-Pro and Val-Pro-Pro tripeptide-containing milk product has acute blood pressure lowering effects in mildly hypertensive subjects.

Casein-derived tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro) lower blood pressure (BP) in long-term clinical studies. Their acute effects on BP and vascular function, important for daily dosing scheme, were studied in a placebo-controlled double-blind crossover study using a single oral dose of a fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro as well as plant sterols. Twenty-five subjects with untreated mild hypertension received in random order 250 g of study product (25 mg peptides and 2 g plant sterols) or placebo. Ambulatory BP was monitored for 8 h post-dose and arterial stiffness measured by pulse wave analysis at 2, 4, and 8 h. Blood and urine samples were analyzed for markers of the renin-angiotensin system (RAS) and endothelial function. Baseline adjusted treatment effect for systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial BP was -2.1 mmHg (95% CI: -4.1 to -0.1, p = 0.045), -1.6 mmHg (95% CI: -3.1 to -0.1, p = 0.03), and -1,9 mmHg (95% CI: -3-3 to -0.4, p = 0.0093), respectively, in favor of the active treatment for 8 h post- dose. No significant differences between the treatments were seen in brachial or aortic augmentation index, pulse wave velocity, or markers of RAS. Urinary excretion of cGMP, the second messenger of endothelial nitric oxide, was higher in the active group vs. placebo (p = 0.01). The results indicate that a single dose of a fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro and plant sterols acutely lowers brachial SBP and DBP in mildly hypertensive subjects.

A spread containing bioactive milk peptides Ile-Pro-Pro and Val-Pro-Pro, and plant sterols has antihypertensive and cholesterol-lowering effects.

Lifestyle intervention is recommended as the primary treatment for mild hypertension and hypercholesterolemia. We studied the effects of a spread containing bioactive milk peptides IPP and VPP, as well as plant sterols, on cardiovascular risk factors in 104 hypertensive, hypercholesterolemic subjects in a randomised, placebo-controlled double-blind intervention. Middle-aged subjects consumed 20 g day⁻¹ of a spread containing 4.2 mg of IPP and VPP as well as 2 g of plant sterols for 10 weeks after a 2 week run-in period. Blood pressure was measured at home 3 times a week. Office blood pressure and 24 h ambulatory blood pressure measurements were performed at the end of the run-in and intervention periods. Blood samples were analysed for serum lipids, plasma glucose and inflammation markers. A significant decrease (-4.1 mmHg vs. -0.5 mmHg, p = 0.007) in systolic blood pressure was seen in the active group, compared to placebo at home measurements. Office blood pressure and 24 h nighttime or daytime ambulatory systolic or diastolic pressure did not differ between the groups. Total (-0.16 vs. 0.25 mmol l⁻¹, p = 0.005) and LDL cholesterol (-0.16 vs. 0.18 mmol l⁻¹, p = 0.006) decreased significantly in the active group compared to the placebo. No significant differences between groups were seen for plasma glucose or inflammation markers. The results thus suggest that milk peptides IPP and VPP and plant sterols, in a low-fat spread matrix, produce a clinically significant reduction in systolic blood pressure as well as serum total and LDL cholesterol without adverse effects. Functional foods that affect 2 major risk factors offer a safe and convenient way to reduce the risk of cardiovascular disease by supporting lifestyle intervention.

Single nucleotide polymorphism -799C/T in matrix metalloproteinase-8 promoter region in arterial disease.

Arterial disease is associated with elevated serum matrix metalloproteinase (MMP)-8 concentration. We studied the role of two promoter region single nucleotide polymorphisms (SNPs) of MMP-8 gene in the arterial disease. The population comprised patients with arterial disease (n = 124) and healthy blood donors (n = 100) as a reference group for MMP-8 SNPs (-799C/T and -381A/G) genotypes and serum concentrations. Genotype frequencies for MMP-8 -799C/T SNP in arterial disease were C/C (43.5%), C/T (32.3%) and T/T (24.2%), and in the reference group they were C/C (50.0%), C/T (40.0%) and T/T (10.0%; P = 0.012). The -799C allele frequency was lower in the patients (59.7%) than in the reference group (70.0%; P = 0.023). The -799C allele showed protective effects against the arterial disease with an odds ratio [95% confidence interval (CI)] of 0.372 (0.141-0.980, P = 0.045) after adjustment for age, gender, and serum MMP-8 and TIMP-1 concentrations. Only in the reference group and whole study population (n = 224), the -799TT genotype significantly associated with an increase in serum MMP-8 concentrations (P = 0.047, 0.025). The -799C allele appeared protective against the arterial disease. The genotype may have an effect on systemic MMP-8 levels which could not, however, be seen in the arterial disease patients probably as a result of the strong inflammation involved in the disease pathogenesis.

Plant sterols and casein-derived tripeptides attenuate blood pressure increase in spontaneously hypertensive rats.

In this study, we investigated the synergistic effects of plant sterols (PS) and casein-derived tripeptides on arterial tone and blood pressure in experimental hypertension. We hypothesized that PS and tripeptides could have positive, synergistic effects on the development of hypertension and endothelial dysfunction in young spontaneously hypertensive rats (SHR). Six-week-old male SHR were divided into 3 groups to receive milk products containing PS, or PS with tripeptides, or a control containing no active components for 8 weeks. Systolic blood pressure (SBP) was measured weekly, and vascular reactivity measurements with isolated mesenteric arteries were performed at the end of the study. Biochemical measurements for several parameters were performed by enzyme-linked immunosorbent assay using plasma samples. Levels of angiotensin-converting enzyme 1, cyclooxygenase-2, endothelial nitric oxide synthase, and P-selectin messenger RNA expressions were determined from aortic tissue by real-time polymerase chain reaction. The study showed that long-term treatment with PS + tripeptides attenuated the development of hypertension in SHR (SBP, 187 ± 5 mm Hg vs 169 ± 4 mm Hg in control group; P < .01). Plant sterols alone did not affect SBP significantly. Endothelial dysfunction was observed in all SHR; however, treatment with PS resulted in poorer endothelium-dependent and nitric oxide-mediated relaxation compared with other groups. Aortic cyclooxygenase-2 and P-selectin were significantly down-regulated in PS and PS + tripeptides groups when compared with the control group. The expression of endothelial nitric oxide synthase was significantly lower in PS than in PS + tripeptides group. In conclusion, long-term treatment with PS has a slight but not significant antihypertensive effect. Plant sterols do not provide any beneficial effects on endothelial function in hypertensive rats; however, treatment with both PS and tripeptides showed mild anti-inflammatory effects.