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. 2013 Apr;114(8):979-87.
doi: 10.1152/japplphysiol.01506.2012. Epub 2013 Feb 21.

Vitamin D signaling pathway plays an important role in the development of heart failure after myocardial infarction

Soochan Bae  1 , Sylvia S Singh, Hyeon Yu, Ji Yoo Lee, Byung Ryul Cho, Peter M Kang
Affiliations

Vitamin D signaling pathway plays an important role in the development of heart failure after myocardial infarction

Soochan Bae et al. J Appl Physiol (1985). 2013 Apr.

Abstract

Accumulating evidence suggests that vitamin D deficiency plays a crucial role in heart failure. However, whether vitamin D signaling itself plays an important role in cardioprotection is poorly understood. In this study, we examined the mechanism of modulating vitamin D signaling on progression to heart failure after myocardial infarction (MI) in mice. Vitamin D signaling was activated by administration of paricalcitol (PC), an activated vitamin D analog. Wild-type (WT) mice underwent sham or MI surgery and then were treated with either vehicle or PC. Compared with vehicle group, PC attenuated development of heart failure after MI associated with decreases in biomarkers, apoptosis, inflammation, and fibrosis. There was also improvement of cardiac function with PC treatment after MI. Furthermore, vitamin D receptor (VDR) mRNA and protein levels were restored by PC treatment. Next, to explore whether defective vitamin D signaling exhibited deleterious responses after MI, WT and VDR knockout (KO) mice underwent sham or MI surgery and were analyzed 4 wk after MI. VDR KO mice displayed a significant decline in survival rate and cardiac function compared with WT mice after MI. VDR KO mice also demonstrated a significant increase in heart failure biomarkers, apoptosis, inflammation, and fibrosis. Vitamin D signaling promotes cardioprotection after MI through anti-inflammatory, antifibrotic and antiapoptotic mechanisms.

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Figures

Fig. 1.
Fig. 1.
Effect of paricalcitol (PC) therapy after myocardial infarction (MI) in vitro and in vivo. A–B: effect of PC on Caspase-3 activity (A) and poly(ADP-ribose) polymerase (PARP)-1 activity (B) after H2O2 (0.1 mM) in adult cardiomyocytes. [N = 4/group; *P < 0.05 vs. vehicle (Veh), †P < 0.05 vs. Veh-H2O2]. C–D: heart weight over body weight (HW/BW) ratio (C), and lung weight over body weight (LUW/BW) ratio (D) in sham and MI groups with or without PC. (N = 4–6 mice in each group; *P < 0.05 vs. sham of each group, †P < 0.05 vs. Veh-MI). E: representative image of heart failure markers, atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) in sham and MI groups with or without PC. F: quantitative analysis of heart failure markers, ANF and BNP. (N = 4–6 mice in each group; *P < 0.05 vs. sham of each group, †P < 0.05 vs. Veh-MI). G: representative photomicrographs from histological sections stained with Masson's Trichrome. H: infarct size analysis of sham and MI with and without PC.
Fig. 2.
Fig. 2.
Effect of PC on mRNA expression of biochemical markers of fibrosis, inflammation, and renin-angiotensin system (RAS) after MI. A: representative mRNA expression of collagenase (COL) 1A1 and 3A1. B: quantitative analysis of mRNA expression of collagenase 1A1 and 3A1. (N = 4–6 mice in each group; *P < 0.05 vs. sham of each group, †P < 0.05 vs. Veh-MI). C: representative image of inflammatory markers, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) in sham and MI groups with or without PC. D: quantitative analysis of inflammatory markers, TNF-α and MCP-1. (N = 4–6 mice in each group; *P < 0.05 vs. sham of each group, †P < 0.05 vs. Veh-MI) E: representative image of RAS genes [angiotensinogen (ANGTSN), renin, and renin receptor (ReninR)] in sham and MI groups with or without PC. F: quantitative analysis of RAS genes (N = 4–6 mice in each group; *P < 0.05 vs. sham of each group, †P < 0.05 vs. Veh-MI).
Fig. 3.
Fig. 3.
Effect of PC on apoptosis and cardiac function after MI. A: representative terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining of cardiomyocytes in sham and MI groups with or without PC. B: quantification of TUNEL-positive cardiomyocytes/total cells. (N = 4–6 mice in each group; *P < 0.05 vs. sham of each group, †P < 0.05 vs. Veh-MI). C–F: hemodynamic measurements by pressure-volume (PV) loop after MI, cardiac output (CO), stroke work (SW), stroke volume (SV), and tau (τ) in sham and MI groups with or without PC. (N = 4–6 mice in each group; *P < 0.05 vs. sham of each group, †P < 0.05 vs. Veh-MI).
Fig. 4.
Fig. 4.
Effect of PC on mRNA and protein expression of vitamin D receptor(VDR) after MI. A: representative image of tissue mRNA level of VDR in sham and MI groups with or without PC. B: quantitative analysis of tissue mRNA level of VDR. (N = 4–6 mice in each group; *P < 0.05 vs. sham of each group, **P < 0.05 vs. Veh-sham, †P < 0.05 vs. Veh-MI). C: representative image of tissue protein level of VDR in sham and MI groups with or without PC. D: quantitative analysis of tissue protein level of VDR. (N = 4–6 mice in each group; *P < 0.05 vs. sham of each group, **P < 0.05 vs. Veh-Sham, †P < 0.05 vs. Veh-MI). WT, wild-type.
Fig. 5.
Fig. 5.
Effect of defective vitamin D signaling on heart failure after MI. A: VDR protein expression in WT and VDR knockout (KO) mice heart. B–C: HW/BW ratio (B) and LUW/BW ratio (C) in sham and MI groups. (N = 4–6 mice in each group; *P < 0.05 vs. sham of each group, †P < 0.05 vs. WT-MI). D: representative image of tissue mRNA level of ANF and BNP in sham and MI groups. E: quantitative analysis of tissue mRNA level of ANF and BNP. (N = 4–6 mice in each group; *P < 0.05 vs. sham of each group, †P < 0.05 vs. WT-MI). F: representative image of tissue mRNA level of TNF-α and MCP-1 in sham and MI groups. G: quantitative analysis of tissue mRNA level of TNF-α and MCP-1. (N = 4–6 mice in each group; *P < 0.05 vs. sham of each group, †P < 0.05 vs. WT-MI).
Fig. 6.
Fig. 6.
Effect of defective vitamin D signaling on apoptosis, cardiac function, and survival rates after MI. A: representative TUNEL staining of cardiomyocytes in sham and MI groups. B: quantification of TUNEL-positive cardiomyocytes/total cells. (N = 4–6 mice in each group; *P < 0.05 vs. sham of each group, †P < 0.05 vs. WT MI). C–F: hemodynamic measurements by PV loop in sham and MI groups. (N = 4–6 mice in each group; *P < 0.05 vs. sham of each group, †P < 0.05 vs. WT MI). G: survival rates after MI in WT and VDR KO mice. Survival curves up to 4 wk after MI were created by Kaplan-Meier method and compared by a log-rank test. (N = 10–15 mice in each group; *P < 0.05 vs. sham of each group, †P < 0.05 vs. WT-MI).
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