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Cited by 35Nitric Oxide and Endothelin EffectsCardiovascular Function and Risk FactorsFolate and B Vitamins Research

Folic acid reverses nitric oxide synthase uncoupling and prevents cardiac dysfunction in insulin resistance: Role of Ca2+/calmodulin-activated protein kinase II

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Roe, Nathan D., He, Emily Y., Wu, Zhenbiao, Ren, Jun·2013·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2013.06.042PMC PMC3859865
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Abstract

Nitric oxide synthase (NOS) may be uncoupled to produce superoxide rather than nitric oxide (NO) under pathological conditions such as diabetes mellitus and insulin resistance, leading to cardiac contractile anomalies. Nonetheless, the role of NOS uncoupling in insulin resistance-induced cardiac dysfunction remains elusive. Given that folic acid may produce beneficial effects for cardiac insufficiency partially through its NOS recoupling capacity, this study was designed to evaluate the effect of folic acid on insulin resistance-induced cardiac contractile dysfunction in a sucrose-induced insulin resistance model. Mice were fed a sucrose or starch diet for 8 weeks before administration of folic acid in drinking water for an additional 4 weeks. Cardiomyocyte contractile and Ca(2+) transient properties were evaluated and myocardial function was assessed using echocardiography. Our results revealed whole body insulin resistance after sucrose feeding associated with diminished NO production, elevated peroxynitrite (ONOO(-)) levels, and impaired echocardiographic and cardiomyocyte function along with a leaky ryanodine receptor (RYR) and intracellular Ca(2+) handling derangement. Western blot analysis showed that insulin resistance significantly promoted Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylation, which might be responsible for the leaky RYR and cardiac mechanical dysfunction. NOS recoupling using folic acid reversed insulin resistance-induced changes in NO and ONOO(-), CaMKII phosphorylation, and cardiac mechanical abnormalities. Taken together, these data demonstrated that treatment with folic acid may reverse cardiac contractile and intracellular Ca(2+) anomalies through ablation of CaMKII phosphorylation and RYR Ca(2+) leak.

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  • Ca2+-regulated extramitochondrial enzymes, such as NADPH oxidases and NOS, under physiological and pathological conditions, stimulate ROS formation.

    “Ca2+-regulated extramitochondrial enzymes, such as NADPH oxidases and nitric oxide synthase (NOS) under both physiological and pathological conditions, stimulate ROS formation (Roe et al. 2013).”

    From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Roe et al. 2013

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Authors
Roe, N. D., He, E. Y., Wu, Z., & Ren, J.
Affiliations
  • University of Wyoming (US)
  • Xijing Hospital (CN)
Corresponding author
Ren, Jun
ORCID
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2013-12
Volume
65
Pages
234-243
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2013.06.042
PMC
PMC3859865
OpenAlex
W1981387374
Cited by
35
References
37
Citations by year
2026: 2 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 2 · 2020: 6 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 6 · 2015: 3 · 2014: 1
FWCI
2.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (2p20rr016474-09, 5p20gm103432-23)
  • National Institute of General Medical Sciences (P20-GM-103432, NIHP20GM134012)
  • National Center for Research Resources (P20-RR-016474)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
Keywords
folic acid, nitric oxide synthase uncoupling, insulin resistance, cardiac contractile dysfunction, CaMKII phosphorylation, intracellular calcium homeostasis, peroxynitrite, nitric oxide, sucrose diet, diabetes mellitus, cardiomyocyte function
MeSH terms
Animals, Disease Models, Animal, Folic Acid, Insulin Resistance, Myocardial Contraction, Myocardium, Vitamin B Complex, Blotting, Western, Nitric Oxide Synthase, Ryanodine Receptor Calcium Release Channel, Myocytes, Cardiac, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2

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