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Observational Study
. 2023 Apr 13;18(4):e0284364.
doi: 10.1371/journal.pone.0284364. eCollection 2023.

L-type calcium channel blocker increases VEGF concentrations in retinal cells and human serum

Anmol Kumar  1   2   3 , Stefan Mutter  1   2   3 , Erika B Parente  1   2   3 , Valma Harjutsalo  1   2   3 , Raija Lithovius  1   2   3 , Sinnakaruppan Mathavan  4 , Markku Lehto  1   2   3 , Timo P Hiltunen  2   5 , Kimmo K Kontula  2   5 , Per-Henrik Groop  1   2   3   6
Affiliations
Observational Study

L-type calcium channel blocker increases VEGF concentrations in retinal cells and human serum

Anmol Kumar et al. PLoS One. .

Abstract

Objective: Vascular endothelial growth factor (VEGF) plays a key role in diabetic retinopathy (DR). Previously, we have reported an association between mutations in a gene coding for the L-type calcium channel subunit, VEGF and DR. L-type calcium channel blockers (LTCCBs) have been widely used as antihypertensive medication (AHM), but their association with VEGF and DR is still unclear. Therefore, we explored the effect of LTCCBs compared to other AHMs on VEGF concentrations in retinal cells and human serum. Furthermore, we evaluated the association between the use of LTCCBs and the risk of severe diabetic eye disease (SDED).

Research design and methods: Müller cells (MIO-M1) were cultured as per recommended protocol and treated with LTCCBs and other AHMs. VEGF secreted from cells were collected at 24 hours intervals. In an interventional study, 39 individuals received LTCCBs or other AHM for four weeks with a four-week wash-out placebo period between treatments. VEGF was measured during the medication and placebo periods. Finally, we evaluated the risk of SDED associated with LTCCB usage in 192 individuals from the FinnDiane Study in an observational setting.

Results: In the cell cultures, the medium VEGF concentration increased time-dependently after amlodipine (P<0.01) treatment, but not after losartan (P>0.01), or lisinopril (P>0.01). Amlodipine, but no other AHM, increased the serum VEGF concentration (P<0.05) during the interventional clinical study. The usage of LTCCB was not associated with the risk of SDED in the observational study.

Conclusions: LTCCB increases VEGF concentrations in retinal cells and human serum. However, the usage of LTCCBs does not appear to be associated with SDED in adults with type 1 diabetes.

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Conflict of interest statement

EBP reports receiving lecture honorariums from Eli Lilly, Abbott, Astra Zeneca, Sanofi, Boehringer Ingelheim and is an advisory board member of Sanofi. PHG reports receiving lecture honorariums from Astellas, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Elo Water, Medscape, MSD, Mundipharma, Novo Nordisk, PeerVoice, Sanofi, Sciarc, and being an advisory board member of Astellas, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Medscape, MSD, Mundipharma, Novo Nordisk, and Sanofi. This does not alter our adherence to PLOS ONE policies on sharing data and materials. AK, SM, TH, VH, RL, SiMa, CF, ML and KK declare no conflict of interest.

Figures

Fig 1
Fig 1
A: Schematic diagram showing the experimental setup and the sample collection timeline. B: Vertical bars represent the mean and the standard deviation of fold changes in the VEGF concentrations in the MIO-M1 cell culture medium at different time points (24 hours, 48 hours, 72 hours and 96 hours) after treatment with amlodipine (10 μM) vs control. Fold changes in the VEGF concentration are calculated by dividing the concentration at a timepoint by the mean control concentration of 125.8765 pg/ml. *P-value = 0.007937.
Fig 2
Fig 2
A: Schematic diagram showing the interventional clinical study design and the sample collection timeline. B: Median and interquartile range changes in the serum VEGF concentration after 4 weeks of daily monotherapies with amlodipine (5 mg), bisoprolol (5 mg), hydrochlorothiazide (25 mg) or losartan (50 mg) compared to the wash-out phases. The nonparametric Wilcoxon signed ranks test was used to test the statistical significance of the drug-induced changes in serum VEGF. *P-value < 0.05 denotes statistical significance.
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