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Homocysteine affects cardiomyocyte viability: concentration-dependent effects on reversible flip-flop, apoptosis and necrosis.
Apoptosis. 2007 Aug; 12(8):1407-18.A

Abstract

BACKGROUND

Hyperhomocysteinaemia (HHC) is thought to be a risk factor for cardiovascular disease including heart failure. While numerous studies have analyzed the role of homocysteine (Hcy) in the vasculature, only a few studies investigated the role of Hcy in the heart. Therefore we have analyzed the effects of Hcy on isolated cardiomyocytes.

METHODS

H9c2 cells (rat cardiomyoblast cells) and adult rat cardiomyocytes were incubated with Hcy and were analyzed for cell viability. Furthermore, we determined the effects of Hcy on intracellular mediators related to cell viability in cardiomyocytes, namely NOX2, reactive oxygen species (ROS), mitochondrial membrane potential (DeltaPsi (m)) and ATP concentrations.

RESULTS

We found that incubation of H9c2 cells with 0.1 mM D,L-Hcy (= 60 microM L-Hcy) resulted in an increase of DeltaPsi (m) as well as ATP concentrations. 1.1 mM D,L-Hcy (= 460 microM L-Hcy) induced reversible flip-flop of the plasma membrane phospholipids, but not apoptosis. Incubation with 2.73 mM D,L-Hcy (= 1.18 mM L-Hcy) induced apoptosis and necrosis. This loss of cell viability was accompanied by a thread-to-grain transition of the mitochondrial reticulum, ATP depletion and nuclear NOX2 expression coinciding with ROS production as evident from the presence of nitrotyrosin residues. Notably, only at this concentration we found a significant increase in S-adenosylhomocysteine which is considered the primary culprit in HHC.

CONCLUSION

We found concentration-dependent effects of Hcy in cardiomyocytes, varying from induction of reversible flip-flop of the plasma membrane phospholipids, to apoptosis and necrosis.

Authors+Show Affiliations

Department of Pathology, VU University Medical Centre, Room 0E46, De Boelelaan 1117, Amsterdam, 1081 HV, The Netherlands. j.sipkens@vumc.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17440815

Citation

Sipkens, Jessica A., et al. "Homocysteine Affects Cardiomyocyte Viability: Concentration-dependent Effects On Reversible Flip-flop, Apoptosis and Necrosis." Apoptosis : an International Journal On Programmed Cell Death, vol. 12, no. 8, 2007, pp. 1407-18.
Sipkens JA, Krijnen PA, Meischl C, et al. Homocysteine affects cardiomyocyte viability: concentration-dependent effects on reversible flip-flop, apoptosis and necrosis. Apoptosis. 2007;12(8):1407-18.
Sipkens, J. A., Krijnen, P. A., Meischl, C., Cillessen, S. A., Smulders, Y. M., Smith, D. E., Giroth, C. P., Spreeuwenberg, M. D., Musters, R. J., Muller, A., Jakobs, C., Roos, D., Stehouwer, C. D., Rauwerda, J. A., van Hinsbergh, V. W., & Niessen, H. W. (2007). Homocysteine affects cardiomyocyte viability: concentration-dependent effects on reversible flip-flop, apoptosis and necrosis. Apoptosis : an International Journal On Programmed Cell Death, 12(8), 1407-18.
Sipkens JA, et al. Homocysteine Affects Cardiomyocyte Viability: Concentration-dependent Effects On Reversible Flip-flop, Apoptosis and Necrosis. Apoptosis. 2007;12(8):1407-18. PubMed PMID: 17440815.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Homocysteine affects cardiomyocyte viability: concentration-dependent effects on reversible flip-flop, apoptosis and necrosis. AU - Sipkens,Jessica A, AU - Krijnen,Paul A J, AU - Meischl,Christof, AU - Cillessen,Saskia A G M, AU - Smulders,Yvo M, AU - Smith,Desirée E C, AU - Giroth,Cindy P E, AU - Spreeuwenberg,Marieke D, AU - Musters,René J P, AU - Muller,Alice, AU - Jakobs,Cornelis, AU - Roos,Dirk, AU - Stehouwer,Coen D A, AU - Rauwerda,Jan A, AU - van Hinsbergh,Victor W M, AU - Niessen,Hans W M, PY - 2007/4/19/pubmed PY - 2007/11/9/medline PY - 2007/4/19/entrez SP - 1407 EP - 18 JF - Apoptosis : an international journal on programmed cell death JO - Apoptosis VL - 12 IS - 8 N2 - BACKGROUND: Hyperhomocysteinaemia (HHC) is thought to be a risk factor for cardiovascular disease including heart failure. While numerous studies have analyzed the role of homocysteine (Hcy) in the vasculature, only a few studies investigated the role of Hcy in the heart. Therefore we have analyzed the effects of Hcy on isolated cardiomyocytes. METHODS: H9c2 cells (rat cardiomyoblast cells) and adult rat cardiomyocytes were incubated with Hcy and were analyzed for cell viability. Furthermore, we determined the effects of Hcy on intracellular mediators related to cell viability in cardiomyocytes, namely NOX2, reactive oxygen species (ROS), mitochondrial membrane potential (DeltaPsi (m)) and ATP concentrations. RESULTS: We found that incubation of H9c2 cells with 0.1 mM D,L-Hcy (= 60 microM L-Hcy) resulted in an increase of DeltaPsi (m) as well as ATP concentrations. 1.1 mM D,L-Hcy (= 460 microM L-Hcy) induced reversible flip-flop of the plasma membrane phospholipids, but not apoptosis. Incubation with 2.73 mM D,L-Hcy (= 1.18 mM L-Hcy) induced apoptosis and necrosis. This loss of cell viability was accompanied by a thread-to-grain transition of the mitochondrial reticulum, ATP depletion and nuclear NOX2 expression coinciding with ROS production as evident from the presence of nitrotyrosin residues. Notably, only at this concentration we found a significant increase in S-adenosylhomocysteine which is considered the primary culprit in HHC. CONCLUSION: We found concentration-dependent effects of Hcy in cardiomyocytes, varying from induction of reversible flip-flop of the plasma membrane phospholipids, to apoptosis and necrosis. SN - 1360-8185 UR - https://www.unboundmedicine.com/medline/citation/17440815/Homocysteine_affects_cardiomyocyte_viability:_concentration_dependent_effects_on_reversible_flip_flop_apoptosis_and_necrosis_ L2 - https://doi.org/10.1007/s10495-007-0077-5 DB - PRIME DP - Unbound Medicine ER -