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  1. AU="Tapio, Joona"
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  3. AU="Blank, Marissa Cathleen"
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  1. Article ; Online: Hemoglobin levels are associated with retinal vascular caliber in a middle-aged birth cohort.

    Sakko, Samuli / Karpale, Mikko / Tapio, Joona / Leppänen, Iina / Ahokas, Oona / Saarela, Ville / Liinamaa, M Johanna / Koivunen, Peppi

    Scientific reports

    2024  Volume 14, Issue 1, Page(s) 9092

    Abstract: Vascular and neural structures of the retina can be visualized non-invasively and used to predict ocular and systemic pathologies. We set out to evaluate the association of hemoglobin (Hb) levels within the national reference interval with retinal ... ...

    Abstract Vascular and neural structures of the retina can be visualized non-invasively and used to predict ocular and systemic pathologies. We set out to evaluate the association of hemoglobin (Hb) levels within the national reference interval with retinal vascular caliber, optical coherence tomography (OCT) and visual field (VF) parameters in the Northern Finland 1966 Birth Cohort (n = 2319, 42.1% male, average age 47 years). The studied parameters were evaluated in Hb quintiles and multivariable linear regression models. The lowest Hb quintile of both sexes presented the narrowest central retinal vein equivalent (CRVE) and the healthiest cardiometabolic profile compared to the other Hb quintiles. In the regression models, CRVE associated positively with Hb levels in both sexes, (B
    MeSH term(s) Middle Aged ; Female ; Humans ; Male ; Birth Cohort ; Eye Diseases/pathology ; Retina/diagnostic imaging ; Cardiovascular Diseases/pathology ; Hemoglobins ; Retinal Vessels/diagnostic imaging ; Retinal Vessels/pathology
    Chemical Substances Hemoglobins
    Language English
    Publishing date 2024-04-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-024-59688-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Lower hemoglobin levels associate with higher baroreflex sensitivity and heart rate variability.

    Tapio, Joona / Kiviniemi, Antti M / Perkiömäki, Juha / Junttila, M Juhani / Huikuri, Heikki V / Ukkola, Olavi / Koivunen, Peppi / Tulppo, Mikko P

    American journal of physiology. Heart and circulatory physiology

    2023  Volume 325, Issue 4, Page(s) H629–H634

    Abstract: The aim of this study was to cross-sectionally examine whether hemoglobin (Hb) levels within the normal variation associate with heart rate variability (HRV) measures and baroreflex sensitivity (BRS). The study population included 733 Finnish subjects of ...

    Abstract The aim of this study was to cross-sectionally examine whether hemoglobin (Hb) levels within the normal variation associate with heart rate variability (HRV) measures and baroreflex sensitivity (BRS). The study population included 733 Finnish subjects of the OPERA cohort (aged 41-59 yr, 53% males, 51.7% treated for hypertension) of whom HRV was measured from a standardized 45-min period and whose Hb levels were within the Finnish reference intervals. The low Hb tertile (mean Hb, 135 g/L) had an overall healthier metabolic profile compared with the high Hb tertile (mean Hb, 152 g/L). BRS was higher in the low Hb tertile compared with the high Hb tertile (
    MeSH term(s) Male ; Middle Aged ; Humans ; Female ; Heart Rate/physiology ; Baroreflex/physiology ; Hypertension ; Autonomic Nervous System ; Heart ; Blood Pressure/physiology
    Language English
    Publishing date 2023-08-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 603838-4
    ISSN 1522-1539 ; 0363-6135
    ISSN (online) 1522-1539
    ISSN 0363-6135
    DOI 10.1152/ajpheart.00415.2023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uc I Zs.89: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Higher hemoglobin levels are an independent risk factor for adverse metabolism and higher mortality in a 20-year follow-up.

    Tapio, Joona / Vähänikkilä, Hannu / Kesäniemi, Y Antero / Ukkola, Olavi / Koivunen, Peppi

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 19936

    Abstract: The aim of this study was to cross-sectionally and longitudinally examine whether higher hemoglobin (Hb) levels within the normal variation associate with key components of metabolic syndrome and total and cardiovascular mortality. The study included 967 ...

    Abstract The aim of this study was to cross-sectionally and longitudinally examine whether higher hemoglobin (Hb) levels within the normal variation associate with key components of metabolic syndrome and total and cardiovascular mortality. The study included 967 Finnish subjects (age 40-59 years) followed for ≥ 20 years. The focus was on Hb levels, cardiovascular diseases (CVDs) and mortality rates. Higher Hb levels associated positively with key anthropometric and metabolic parameters at baseline. At the follow-up similar associations were seen in men. The highest Hb quartile showed higher leptin levels and lower adiponectin levels at baseline and follow-up (p < 0.05) and lower plasma ghrelin levels at baseline (p < 0.05). Higher baseline Hb levels associated independently with prevalence of type 2 diabetes at follow-up (p < 0.01). The highest Hb quartile associated with higher serum alanine aminotransferase levels (p < 0.001) and independently with increased risk for liver fat accumulation (OR 1.63 [1.03; 2.57]) at baseline. The highest Hb quartile showed increased risk for total (HR = 1.48 [1.01; 2.16]) and CVD-related mortality (HR = 2.08 [1.01; 4.29]). Higher Hb levels associated with an adverse metabolic profile, increased prevalence of key components of metabolic syndrome and higher risk for CVD-related and total mortality.
    MeSH term(s) Adiponectin/blood ; Adult ; Aged ; Cardiovascular Diseases/mortality ; Cause of Death ; Diabetes Mellitus, Type 2/epidemiology ; Female ; Finland/epidemiology ; Follow-Up Studies ; Ghrelin/blood ; Hemoglobins/analysis ; Humans ; Leptin/blood ; Male ; Metabolic Syndrome/epidemiology ; Middle Aged ; Risk Factors
    Chemical Substances Adiponectin ; Ghrelin ; Hemoglobins ; Leptin
    Language English
    Publishing date 2021-10-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-99217-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Contribution of HIF-P4H isoenzyme inhibition to metabolism indicates major beneficial effects being conveyed by HIF-P4H-2 antagonism.

    Tapio, Joona / Halmetoja, Riikka / Dimova, Elitsa Y / Mäki, Joni M / Laitala, Anu / Walkinshaw, Gail / Myllyharju, Johanna / Serpi, Raisa / Koivunen, Peppi

    The Journal of biological chemistry

    2022  Volume 298, Issue 8, Page(s) 102222

    Abstract: Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases (HIF-P4Hs 1-3) are druggable targets in renal anemia, where pan-HIF-P4H inhibitors induce an erythropoietic response. Preclinical data suggest that HIF-P4Hs could also be therapeutic targets for ... ...

    Abstract Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases (HIF-P4Hs 1-3) are druggable targets in renal anemia, where pan-HIF-P4H inhibitors induce an erythropoietic response. Preclinical data suggest that HIF-P4Hs could also be therapeutic targets for treating metabolic dysfunction, although the contributions of HIF-P4H isoenzymes in various tissues to the metabolic phenotype are inadequately understood. Here, we used mouse lines that were gene-deficient for HIF-P4Hs 1 to 3 and two preclinical pan-HIF-P4H inhibitors to study the contributions of these isoenzymes to the anthropometric and metabolic outcome and HIF response. We show both inhibitors induced a HIF response in wildtype white adipose tissue (WAT), liver, and skeletal muscle and alleviated metabolic dysfunction during a 6-week treatment period, but they did not alter healthy metabolism. Our data indicate that HIF-P4H-1 contributed especially to skeletal muscle and WAT metabolism and that its loss lowered body weight and serum cholesterol levels upon aging. In addition, we found HIF-P4H-3 had effects on the liver and WAT and its loss increased body weight, adiposity, liver weight and triglyceride levels, WAT inflammation, and cholesterol levels and resulted in hyperglycemia and insulin resistance, especially during aging. Finally, we demonstrate HIF-P4H-2 affected all tissues studied; its inhibition lowered body and liver weight and serum cholesterol levels and improved glucose tolerance. We found very few HIF target metabolic mRNAs were regulated by the inhibition of three isoenzymes, thus suggesting a potential for selective therapeutic tractability. Altogether, these data provide specifications for the future development of HIF-P4H inhibitors for the treatment of metabolic diseases.
    MeSH term(s) Adipose Tissue, White/metabolism ; Aging/metabolism ; Animals ; Body Weight ; Cholesterol/blood ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism ; Insulin Resistance ; Isoenzymes/antagonists & inhibitors ; Isoenzymes/metabolism ; Liver/metabolism ; Mice ; Muscle, Skeletal/metabolism ; Obesity/metabolism
    Chemical Substances Hypoxia-Inducible Factor 1, alpha Subunit ; Isoenzymes ; Cholesterol (97C5T2UQ7J) ; Hypoxia-Inducible Factor-Proline Dioxygenases (EC 1.14.11.29)
    Language English
    Publishing date 2022-07-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2022.102222
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    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.108: Show issues Location:
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  5. Article ; Online: Activation of the hypoxia response pathway protects against age-induced cardiac hypertrophy.

    Röning, Tapio / Magga, Johanna / Laitakari, Anna / Halmetoja, Riikka / Tapio, Joona / Dimova, Elitsa Y / Szabo, Zoltan / Rahtu-Korpela, Lea / Kemppi, Anna / Walkinshaw, Gail / Myllyharju, Johanna / Kerkelä, Risto / Koivunen, Peppi / Serpi, Raisa

    Journal of molecular and cellular cardiology

    2021  Volume 164, Page(s) 148–155

    Abstract: Aims: We have previously demonstrated protection against obesity, metabolic dysfunction, atherosclerosis and cardiac ischemia in a hypoxia-inducible factor (HIF) prolyl 4-hydroxylase-2 (Hif-p4h-2) deficient mouse line, attributing these protective ... ...

    Abstract Aims: We have previously demonstrated protection against obesity, metabolic dysfunction, atherosclerosis and cardiac ischemia in a hypoxia-inducible factor (HIF) prolyl 4-hydroxylase-2 (Hif-p4h-2) deficient mouse line, attributing these protective effects to activation of the hypoxia response pathway in a normoxic environment. We intended here to find out whether the Hif-p4h-2 deficiency affects the cardiac health of these mice upon aging.
    Methods and results: When the Hif-p4h-2 deficient mice and their wild-type littermates were monitored during normal aging, the Hif-p4h-2 deficient mice had better preserved diastolic function than the wild type at one year of age and less cardiomyocyte hypertrophy at two years. On the mRNA level, downregulation of hypertrophy-associated genes was detected and shown to be associated with upregulation of Notch signaling, and especially of the Notch target gene and transcriptional repressor Hairy and enhancer-of-split-related basic helix-loop-helix (Hey2). Blocking of Notch signaling in cardiomyocytes isolated from Hif-p4h-2 deficient mice with a gamma-secretase inhibitor led to upregulation of the hypertrophy-associated genes. Also, targeting Hey2 in isolated wild-type rat neonatal cardiomyocytes with siRNA led to upregulation of hypertrophic genes and increased leucine incorporation indicative of increased protein synthesis and hypertrophy. Finally, oral treatment of wild-type mice with a small molecule inhibitor of HIF-P4Hs phenocopied the effects of Hif-p4h-2 deficiency with less cardiomyocyte hypertrophy, upregulation of Hey2 and downregulation of the hypertrophy-associated genes.
    Conclusions: These results indicate that activation of the hypoxia response pathway upregulates Notch signaling and its target Hey2 resulting in transcriptional repression of hypertrophy-associated genes and less cardiomyocyte hypertrophy. This is eventually associated with better preserved cardiac function upon aging. Activation of the hypoxia response pathway thus has therapeutic potential for combating age-induced cardiac hypertrophy.
    MeSH term(s) Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cardiomegaly/genetics ; Cardiomegaly/metabolism ; Hypoxia/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Hypoxia-Inducible Factor-Proline Dioxygenases/genetics ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism ; Mice ; Rats ; Signal Transduction
    Chemical Substances Basic Helix-Loop-Helix Transcription Factors ; Hypoxia-Inducible Factor 1, alpha Subunit ; Hypoxia-Inducible Factor-Proline Dioxygenases (EC 1.14.11.29)
    Language English
    Publishing date 2021-12-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80157-4
    ISSN 1095-8584 ; 0022-2828
    ISSN (online) 1095-8584
    ISSN 0022-2828
    DOI 10.1016/j.yjmcc.2021.12.003
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 426: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
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  6. Article ; Online: HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD.

    Laitakari, Anna / Tapio, Joona / Mäkelä, Kari A / Herzig, Karl-Heinz / Dengler, Franziska / Gylling, Helena / Walkinshaw, Gail / Myllyharju, Johanna / Dimova, Elitsa Y / Serpi, Raisa / Koivunen, Peppi

    Journal of molecular medicine (Berlin, Germany)

    2020  Volume 98, Issue 5, Page(s) 719–731

    Abstract: Non-alcoholic fatty liver disease (NAFLD) parallels the global obesity epidemic with unmet therapeutic needs. We investigated whether inhibition of hypoxia-inducible factor prolyl 4-hydroxylase-2 (HIF-P4H-2), a key cellular oxygen sensor whose inhibition ...

    Abstract Non-alcoholic fatty liver disease (NAFLD) parallels the global obesity epidemic with unmet therapeutic needs. We investigated whether inhibition of hypoxia-inducible factor prolyl 4-hydroxylase-2 (HIF-P4H-2), a key cellular oxygen sensor whose inhibition stabilizes HIF, would protect from NAFLD by subjecting HIF-P4H-2-deficient (Hif-p4h-2
    MeSH term(s) Animals ; Biomarkers ; Carbohydrate Metabolism/genetics ; Diet ; Disease Models, Animal ; Disease Susceptibility ; Fructose/metabolism ; Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors ; Hypoxia-Inducible Factor-Proline Dioxygenases/genetics ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism ; Lipid Metabolism ; Lipids/blood ; Liver/metabolism ; Liver/pathology ; Mice ; Mice, Transgenic ; Non-alcoholic Fatty Liver Disease/etiology ; Non-alcoholic Fatty Liver Disease/metabolism ; Non-alcoholic Fatty Liver Disease/pathology ; Thermogenesis/genetics
    Chemical Substances Biomarkers ; Lipids ; Fructose (30237-26-4) ; Hypoxia-Inducible Factor-Proline Dioxygenases (EC 1.14.11.29)
    Language English
    Publishing date 2020-04-15
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1223802-8
    ISSN 1432-1440 ; 0946-2716
    ISSN (online) 1432-1440
    ISSN 0946-2716
    DOI 10.1007/s00109-020-01903-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ua VI Zs.36: Show issues Location:
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  7. Article ; Online: Systematic evaluation of the association between hemoglobin levels and metabolic profile implicates beneficial effects of hypoxia.

    Auvinen, Juha / Tapio, Joona / Karhunen, Ville / Kettunen, Johannes / Serpi, Raisa / Dimova, Elitsa Y / Gill, Dipender / Soininen, Pasi / Tammelin, Tuija / Mykkänen, Juha / Puukka, Katri / Kähönen, Mika / Raitoharju, Emma / Lehtimäki, Terho / Ala-Korpela, Mika / Raitakari, Olli T / Keinänen-Kiukaanniemi, Sirkka / Järvelin, Marjo-Riitta / Koivunen, Peppi

    Science advances

    2021  Volume 7, Issue 29

    Abstract: Activation of the hypoxia-inducible factor (HIF) pathway reprograms energy metabolism. Hemoglobin (Hb) is the main carrier of oxygen. Using its normal variation as a surrogate measure for hypoxia, we explored whether lower Hb levels could lead to ... ...

    Abstract Activation of the hypoxia-inducible factor (HIF) pathway reprograms energy metabolism. Hemoglobin (Hb) is the main carrier of oxygen. Using its normal variation as a surrogate measure for hypoxia, we explored whether lower Hb levels could lead to healthier metabolic profiles in mice and humans (
    MeSH term(s) Animals ; Hemoglobins/genetics ; Hemoglobins/metabolism ; Hypoxia/genetics ; Liver/metabolism ; Metabolome ; Mice ; Oxygen/metabolism
    Chemical Substances Hemoglobins ; Oxygen (S88TT14065)
    Language English
    Publishing date 2021-07-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.abi4822
    Database MEDical Literature Analysis and Retrieval System OnLINE

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