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Fyhrquist F.,Minerva Institute for Medical Research | Fyhrquist F.,University of Helsinki | Tiitu A.,Minerva Institute for Medical Research | Tiitu A.,Folkhalsan Institute of Genetics | And 5 more authors.
Journal of Internal Medicine | Year: 2010

Fyhrquist F, Tiitu A, Saijonmaa O, Forsblom C, Groop P-H, on behalf of the FinnDiane Study Group (Minerva Institute for Medical Research; Helsinki University Central Hospital; and Folkhälsan Institute of Genetics; Helsinki, Finland). Telomere length and progression of diabetic nephropathy in patients with type 1 diabetes. J Intern Med 2010; 267: 278-286. Objectives. To determine whether short telomere length of blood leucocytes from patients with type 1 diabetes is associated with or predictive of progression of diabetic nephropathy. Design and methods. Two consecutive DNA samples were obtained from 132 patients from the nationwide Finnish Diabetic Nephropathy Study with type 1 diabetes. Control DNA samples were taken from 44 healthy blood donors. Telomere length was measured by Southern blot. Patients were divided into three groups according to their urinary albumin excretion rate (AER): 48 patients with normoalbuminuria (AER < 20 μg min -1); seven patients with microalbuminuria (AER ≥ 20 μg min -1 <200 μg min -1) and 77 patients with macroalbuminuria (AER ≥ 200 μg min -1). Progression was defined as a change in albuminuria to a higher level. Results. Progression occurred in 21 patients. Progressors had shorter mean telomere length (8.1 ± 0.7 kb, mean ± SD; P = 0.017) and higher percentage of short telomeres (32.0 ± 8%, P = 0.002) than nonprogressors (8.5 ± 0.7 kb and 27 ± 7.2%, respectively). Thus, both shorter telomeres (HR = 0.190, 95%CI 0.065-0.558, P = 0.0025) and higher proportion of short telomeres (HR = 1.115, 1.039-1.195, P =0.0023) were independent predictors of diabetic nephropathy. Telomere length was not associated with the degree of albuminuria and was not different in patients with type 1 diabetes compared with healthy controls. Conclusions. Short telomeres are independent predictors of progression of diabetic nephropathy in patients with type 1 diabetes. © 2009 Blackwell Publishing Ltd.


Kaartokallio T.,University of Helsinki | Klemetti M.M.,University of Helsinki | Klemetti M.M.,South Karelia Central Hospital | Timonen A.,University of Helsinki | And 14 more authors.
Hypertension | Year: 2014

Preeclampsia is a serious and phenotypically heterogeneous vascular pregnancy disorder. Heme oxygenase-1 (HO-1) is a stress response enzyme that may protect the maternal endothelium and facilitate adequate metabolic adaptation to pregnancy by its antioxidant and anti-inflammatory functions. HO-1 stress response is modulated by HO-1 gene (HMOX1) polymorphisms. Individuals with the long allele of a guanine-thymine (GTn) microsatellite repeat located in the promoter region of HMOX1 have a higher risk of cardiometabolic diseases compared with those with the short allele. We investigated whether the long GTn allele of HMOX1 is associated with subtypes of preeclampsia. The GTn repeat was genotyped in 759 patients and in 779 controls from the Finnish Genetics of Preeclampsia Consortium (FINNPEC) cohort using DNA fragment analysis. In subtype analyses, the long-long (LL) genotype was associated with nonsevere (additive model: odds ratio [OR], 1.94; 95% confidence interval [CI], 1.13-3.31; recessive model: OR, 1.39; 95% CI, 1.02-1.89) and late-onset (additive model: OR, 1.44; 95% CI, 1.02-2.05; recessive model: OR, 1.28; 95% CI, 1.02-1.59) preeclampsia and with preeclampsia without a small-for-gestational- age infant (recessive model: OR, 1.27; 95% CI, 1.02-1.58). The long allele was associated with nonsevere (OR, 1.35; 95% CI, 1.07-1.70) and late-onset (OR, 1.21; 95% CI, 1.03-1.42) preeclampsia and with preeclampsia without a small-for-gestational-age infant (OR, 1.19; 95% CI, 1.02-1.40). Moreover, both the LL genotype and the long allele were associated with preeclampsia in women who had smoked during pregnancy. In conclusion, the GTn long allele seems to predispose to late-onset, less severe form of preeclampsia. This finding supports the role of HO-1 in the pathogenesis of preeclampsia and suggests that the HO-1 pathway may provide a potential target for the treatment of preeclampsia. © 2014 American Heart Association, Inc.


Saukkonen K.,Emergency Care | Lakkisto P.,University of Helsinki | Lakkisto P.,Minerva Institute for Medical Research | Kaunisto M.A.,Folkhalsan Institute of Genetics | And 6 more authors.
Shock | Year: 2010

Heme oxygenase 1 (HO-1) is a cytoprotective enzyme upregulated by various critical illness-related stress stimuli. We investigated the association of HO-1 gene polymorphisms and plasma concentrations with the outcome of critically ill patients in a prospective cohort study of 231 critically ill patients admitted to tertiary care medical and medical-surgical intensive care units. Blood samples were collected on days 1, 2, and 3 to 4 in the intensive care unit. The HO-1 plasma concentration was measured in serial samples, and HO-1 single nucleotide polymorphisms, -413A/T and +99G/C, and HO-1 promoter GTn repeat length polymorphism were determined. The +99C and long GTn alleles were in perfect linkage disequilibrium, and the -413T/GT(L)/+99C haplotype had significant independent effect on first-day HO-1 plasma concentrations in linear regression analysis (P = 0.03) and associated with lower HO-1 plasma levels. Furthermore, -413T/GT(L)/+99C haplotype associated with a lower frequency of multiple-organ dysfunction compared with other haplotypes (P = 0.017). The HO-1 plasma concentrations of study patients were significantly higher than the values of healthy controls at all time points (P < 0.001), and the first-day plasma HO-1 levels were independently associated with the Sequential Organ Failure Assessment score (P = 0.001). In conclusion, the HO-1 -413T/GT(L)/+99C haplotype is associated with HO-1 plasma levels and the frequency of multiple-organ dysfunction in critically ill patients. The HO-1 plasma concentrations are significantly increased among critically ill patients and associated with the degree of organ dysfunction. Copyright © 2010 by the Shock Society.


Tikkanen I.,University of Helsinki | Tikkanen I.,Minerva Institute for Medical Research | Chilton R.,University of Texas Health Science Center at San Antonio | Johansen O.E.,Boehringer Ingelheim | Johansen O.E.,Baerum Hospital
Current Opinion in Nephrology and Hypertension | Year: 2016

Purpose of review: The majority of patients with type 2 diabetes mellitus (T2DM) have hypertension requiring combination therapy. Sodium glucose cotransporter 2 (SGLT2) inhibitors are novel glucose-lowering drugs with shared and potentially unique beneficial effects on cardiovascular risk beyond glycemic control. This review focuses on the potential role of SGLT2 inhibitors in the treatment of hypertension associated with T2DM. Recent findings: SGLT2 inhibitors reduce office SBP by 3-5 mmHg and DBP by 2-3 mmHg across all class members. Corresponding clinically meaningful, significant blood pressure (BP) lowering effects have been confirmed using 24 h ambulatory BP monitoring. SGLT2 inhibitors reduce BP irrespective of the type of background antihypertensive medication. The antihypertensive actions of SGLT2 inhibitors involve several mechanisms including modest diuretic effects, weight loss, and direct vascular effects leading to decreased arterial stiffness and vascular resistance. The first-in class cardiovascular outcome trial with empagliflozin showed a significant reduction in a composite endpoint of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction in T2DM patients at high risk for cardiovascular events. Summary: SGLT2 inhibitors have clinically significant antihypertensive effects. SGLT2 inhibition could be a potentially useful supplement to the BP-lowering treatment armamentarium in patients with T2DM. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Fyhrquist F.,Minerva Institute for Medical Research | Saijonmaa O.,Minerva Institute for Medical Research | Strandberg T.,University of Helsinki
Nature Reviews Cardiology | Year: 2013

Cellular senescence, defined as arrest during the cell cycle (G 0), is involved in the complex process of the biological ageing of tissues, organs, and organisms. Senescence is driven by many factors including oxidative stress, the DNA damage and repair response, inflammation, mitogenic signals, and telomere shortening. Telomeres are shortened by each cell division until a critical length is reached and dysfunction ensues. DNA-repair pathways are then recruited and cells enter senescence, losing their capacity to proliferate. In addition to cell division, factors causing telomere shortening include DNA damage, inflammation, and oxidative stress. Both cardiovascular risk factors and common cardiovascular diseases, such as atherosclerosis, heart failure, and hypertension, are associated with short leucocyte telomeres, but causality remains undetermined. Telomere length does not satisfy strict criteria for being a biomarker of ageing, but adds predictive power to that of chronological age, and can be considered a marker of cardiovascular ageing. The 'senescence-associated secretory phenotype' of senescent cells exerts a wide range of autocrine and paracrine activities aimed at tissue repair, but which also fuel degenerative and proliferative alterations that contribute to cardiovascular disease. In this Review, the relationship between telomere shortening, senescence, and cardiovascular disease is discussed. © 2013 Macmillan Publishers Limited.


Augustin M.,University of Helsinki | Mahar M.A.A.,University of Helsinki | Lakkisto P.,Minerva Institute for Medical Research | Lakkisto P.,University of Helsinki | And 5 more authors.
Journal of Tissue Engineering and Regenerative Medicine | Year: 2013

Cell sheet-based tissue engineering shows great potential in the treatment of ischaemic heart disease. However, treatment efficacy is compromised by low blood and nutrient supply. The aim of this study was to investigate the effect of pro-angiogenic vascular endothelial growth factor (VEGF)-modified mesenchymal stem cell (MSC) sheet transplantation therapy in ischaemic heart failure. Rat MSCs were manipulated to overexpress the VEGF gene. In vitro, the antiapoptotic and paracrine effects were assessed under hypoxic conditions. In vivo, we evaluated the therapeutic effect of VEGF-modified MSC sheet therapy in a rat model of acute myocardial infarction (AMI). Forty-five Wistar rats were divided into three groups; one group underwent AMI (control), another underwent AMI and WT sheet transplantation (WT-MSC) and a third group underwent AMI and VEGF sheet transplantation (VEGF-MSC). Echocardiography was performed after 3, 10 and 28days. Samples for histological analysis were collected at the end of the study. The VEGF gene protected MSCs against apoptosis. In vitro, VEGF overexpression significantly reduced MSC apoptosis compared with wild-type and enhanced VEGF secretion under hypoxic conditions. Capillary density in the infarct border zone was higher in VEGF-MSC-transplanted animals than in WT-MSC-treated animals. Furthermore, VEGF-MSC-transplanted animals had a smaller infarct size than WT-MSC-treated animals and exhibited remarkable functional recovery. These findings support the premise that transplantation of proangiogenic gene-modified MSCs may be valuable for mediating substantial functional recovery after AMI. © 2013 John Wiley & Sons, Ltd.


Putula J.,University of Helsinki | Turunen P.M.,University of Helsinki | Johansson L.,Uppsala University | Nasman J.,Åbo Akademi University | And 5 more authors.
FEBS Letters | Year: 2011

We wanted to analyze the basis for the distinction between OX1 and OX2 orexin receptors by the known agonists, orexin-A, orexin-B and Ala11, d-Leu15-orexin-B, of which the latter two show some selectivity for OX2. For this, chimaeric OX1/OX 2 and OX2/OX1 orexin receptors were generated. The receptors were transiently expressed in HEK-293 cells, and potencies of the agonists to elicit cytosolic Ca2+ elevation were measured. The results show that the N-terminal regions of the receptor are most important, and the exchange of the area from the C-terminal part of the transmembrane helix 2 to the transmembrane helix 4 is enough to lead to an almost total change of the receptor's ligand profile. © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.


Siltanen A.,University of Helsinki | Kitabayashi K.,Osaka University | Lakkisto P.,Minerva Institute for Medical Research | Lakkisto P.,University of Helsinki | And 8 more authors.
PLoS ONE | Year: 2011

After severe myocardial infarction (MI), heart failure results from ischemia, fibrosis, and remodeling. A promising therapy to enhance cardiac function and induce therapeutic angiogenesis via a paracrine mechanism in MI is myoblast sheet transplantation. We hypothesized that in a rat model of MI-induced chronic heart failure, this therapy could be further improved by overexpression of the antiapoptotic, antifibrotic, and proangiogenic hepatocyte growth factor (HGF) in the myoblast sheets. We studied the ability of wild type (L6-WT) and human HGF-expressing (L6-HGF) L6 myoblast sheet-derived paracrine factors to stimulate cardiomyocyte, endothelial cell, or smooth muscle cell migration in culture. Further, we studied the autocrine effect of hHGF-expression on myoblast gene expression profiles by use of microarray analysis. We induced MI in Wistar rats by left anterior descending coronary artery (LAD) ligation and allowed heart failure to develop for 4 weeks. Thereafter, we administered L6-WT (n = 15) or L6-HGF (n = 16) myoblast sheet therapy. Control rats (n = 13) underwent LAD ligation and rethoracotomy without therapy, and five rats underwent a sham operation in both surgeries. We evaluated cardiac function with echocardiography at 2 and 4 weeks after therapy, and analyzed cardiac angiogenesis and left ventricular architecture from histological sections at 4 weeks. Paracrine mediators from L6-HGF myoblast sheets effectively induced migration of cardiac endothelial and smooth muscle cells but not cardiomyocytes. Microarray data revealed that hHGF-expression modulated myoblast gene expression. In vivo, L6-HGF sheet therapy effectively stimulated angiogenesis in the infarcted and non-infarcted areas. Both L6-WT and L6-HGF therapies enhanced cardiac function and inhibited remodeling in a similar fashion. In conclusion, L6-HGF therapy effectively induced angiogenesis in the chronically failing heart. Cardiac function, however, was not further enhanced by hHGF expression. © 2011 Siltanen et al.


Sevastianova K.,Minerva Institute for Medical Research | Sevastianova K.,University of Helsinki | Sutinen J.,University of Helsinki | Greco D.,University of Helsinki | And 12 more authors.
Diabetes | Year: 2011

OBJECTIVE - Combination antiretroviral therapy (cART) is associated with lipodystrophy, i.e., loss of subcutaneous adipose tissue in the abdomen, limbs, and face and its accumulation intraabdominally. No fat is lost dorsocervically and it can even accumulate in this region (buffalo hump). It is unknown how preserved dorsocervical fat differs from abdominal subcutaneous fat in HIV-1-infected cART-treated patients with (cART+LD+) and without (cART+LD2) lipodystrophy. RESEARCH DESIGN AND METHODS - We used histology, microarray, PCR, and magnetic resonance imaging to compare dorsocervical and abdominal subcutaneous adipose tissue in cART+LD+ (n = 21) and cART+LD2 (n = 11). RESULTS - Albeit dorsocervical adipose tissue in cART+LD+ seems spared from lipoatrophy, its mitochondrial DNA (mtDNA; copies/cell) content was significantly lower (by 62%) than that of the corresponding tissue in cART+LD2. Expression of CD68 mRNA, a marker of macrophages, and numerous inflammatory genes in microarray were significantly lower in dorsocervical versus abdominal subcutaneous adipose tissue. Genes with the greatest difference in expression between the two depots were those involved in regulation of transcription and regionalization (homeobox genes), irrespective of lipodystrophy status. There was negligible mRNA expression of uncoupling protein 1, a gene characteristic of brown adipose tissue, in either depot. CONCLUSIONS - Because mtDNA is depleted even in the nonatrophic dorsocervical adipose tissue, it is unlikely that the cause of lipoatrophy is loss of mtDNA. Dorsocervical adipose tissue is less inflamed than lipoatrophic adipose tissue. It does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal subcutaneous adipose tissue is in expression of homeobox genes. © 2011 by the American Diabetes Association.


PubMed | Minerva Institute for Medical Research
Type: Journal Article | Journal: Journal of the renin-angiotensin-aldosterone system : JRAAS | Year: 2013

Short telomeres are often associated with cardiovascular risk factors and age-related diseases, while the angiotensin converting enzyme (ACE) gene insertion/deletion polymorphism (DD, ID, II) has shown such associations less consistently. We hypothesized that telomere length and association of telomere length with cardiovascular risk is affected by ACE (I/D) genotype.We measured leucocyte telomere length (LTL) by Southern blot and analysed ACE I/D genotypes in 1249 subjects with hypertension and left ventricular hypertrophy (LVH). We examined interactions of ACE I/D genotype with LTL and cardiovascular risk.Mean LTL in DD or ID genotype was shorter (8.15 and 8.14 kb, respectively), than in II genotype (8.27 kb, p=0.0005). This difference was significant in the younger subjects (55-64 years, p=0.02) but not in the older group (65-80 years, p=0.56 ). In DD but not I/D or II genotype, proportion of short telomeres (<5 kb) was related to Framingham risk score.Shorter LTL in genotypes DD or ID suggests a negative effect of the D allele on telomere length. Homozygocity for the D allele appears to strengthen the association of telomere length with increased cardiovascular risk in elderly hypertensive subjects with LVH.

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