Abstract 15444: Vitamin D Signaling Pathway Plays an Important Role in the Development of Heart Failure After Myocardial Infarction (MI) by Modulating Apoptosis
Vitamin D deficiency has been associated with increased incidence of heart failure, and activation of vitamin D signaling has been shown to have cardioprotective effects. In this study, we examined mechanism of modulating vitamin D signaling on progression to heart failure after myocardial infarction (MI) in mice.
Methods and Results: For a model of activated vitamin D signaling, we treated wild type (WT) mice with paricalcitol (PC), an activated vitamin D analog, before MI. For a model of defective vitamin D signaling, we used vitamin D receptor (VDR) knockout (KO) mice for MI experiment. First, wild type (WT) mice underwent sham or MI operation with either vehicle treatment or PC therapy (15 ng/mouse, i.p., 3x week). MI with PC treatment (MI+PC) resulted in significantly decreased heart weight/tibia length (HW/TL) ratio (-18%, p<0.05) compared with MI with vehicle. There were significant decreases in ANF (-33%), BNP (-29%), and β-MHC (-39%) (p<0.05 for all) levels with PC after MI. Inflammation markers such as TNF-α and MCP-1 also significantly decreased with PC after MI (p<0.05 for both). TUNEL staining also showed that PC after MI significantly attenuated the amount of apoptosis (1.64% vs. 0.39 %, p<0.05). Finally, cardiac function determined using pressure-volume (PV) loop analysis revealed that PC after MI resulted in a significant improvement of cardiac output (CO) (+59%) and stroke volume (SV) (+57%) (p<0.05 for all). Next, we explored if mice lacking the VDR exhibits deleterious response after MI. WT and VDR KO mice received either sham or MI operation and analyzed after 2 days or 4 weeks. VDR KO+MI group showed significant increase of HW/TL ratio (+19%) compared to WT-MI. There were also significant increases in ANF, BNP, and α-MHC, and TNF-α and MCP-1 in VDR KO+MI compared to WT+MI. In addition, there was a significant increase in the amount of apoptosis (1.55 % vs. 4.25%, p<0.05), and significant worsening of cardiac function parameters (-32% in CO and -26% in SV) in VDR KO+MI compared to the WT+MI. Furthermore, survival rate up to 4 weeks after MI significantly decreased in VDR KO compared to WT mice (77 % vs. 54%, p<0.05).
Conclusions: Activation of vitamin D receptor pathway attenuates the progression of heart failure after MI through anti-apoptotic mechanisms.
- Myocardial infarction
- Cardiovascular therapeutics
- Cardiovascular disease prevention
- Drug administration
- © 2011 by American Heart Association, Inc.