Abstract
ABSTRACTMyocardial infarction (MI) is a major cause of death worldwide. Epidemiological studies have linked vitamin D deficiency to MI incidence. Because fibroblast growth factor‐23 (FGF23) is a master regulator of vitamin D hormone production and has been shown to be associated with cardiac hypertrophy per se, we explored the hypothesis that FGF23 may be a previously unrecognized pathophysiological factor causally linked to progression of cardiac dysfunction post‐MI. Here, we show that circulating intact Fgf23 was profoundly elevated, whereas serum vitamin D hormone levels were suppressed, after induction of experimental MI in rat and mouse models, independent of changes in serum soluble Klotho or serum parathyroid hormone. Both skeletal and cardiac expression of Fgf23 was increased after MI. Although the molecular link between the cardiac lesion and circulating Fgf23 concentrations remains to be identified, our study has uncovered a novel heart–bone–kidney axis that may have important clinical implications and may inaugurate the new field of cardio‐osteology. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
Highlights
The prevalence of vitamin D deficiency has been shown to be very high in patients with acute myocardial infarction (MI),(1) and low serum vitamin D has been implicated in epidemiological studies as a risk factor for hypertension, left ventricular hypertrophy, increased arterial stiffness, and endothelial dysfunction in normal subjects and in patients with chronic kidney disease and type 2 diabetes.[2,3,4,5,6,7,8] Experimental studies support a role of vitamin D signaling in the pathophysiology of MI: Vitamin D analogs are cardioprotective in an experimental acute MI model,(9) and global vitamin D receptor (VDR) knockout mice are characterized by decreased survival and impaired cardiac function post-MI, relative to wild-type controls.[9] the mechanisms by which vitamin D may regulate cardiovascular function in MI are still controversial
We recently discovered that vitamin D can regulate endothelial function by modulating the bioavailability of the vasodilator nitric oxide (NO) through transcriptional control of the key NO synthesizing enzyme, endothelial NO synthase.[10]. Mice with a nonfunctioning vitamin D receptor (VDR) showed endothelial dysfunction, increased arterial stiffness, increased aortic impedance, structural remodeling of the aorta, and impaired systolic and diastolic heart function.[10]. Endothelial dysfunction is one of the initial events associated with MI and progression of ischemic heart failure (IHF).(11) In addition, increased arterial stiffness and endothelial dysfunction are related to acute MI incidence and development of chronic heart failure.[12,13]
Serum vitamin D hormone levels were markedly suppressed by about 80% in both MI mice and rats compared with sham controls, 4 weeks post-MI (Fig. 2B)
Summary
The prevalence of vitamin D deficiency has been shown to be very high in patients with acute myocardial infarction (MI),(1) and low serum vitamin D has been implicated in epidemiological studies as a risk factor for hypertension, left ventricular hypertrophy, increased arterial stiffness, and endothelial dysfunction in normal subjects and in patients with chronic kidney disease and type 2 diabetes.[2,3,4,5,6,7,8] Experimental studies support a role of vitamin D signaling in the pathophysiology of MI: Vitamin D analogs are cardioprotective in an experimental acute MI model,(9) and global vitamin D receptor (VDR) knockout mice are characterized by decreased survival and impaired cardiac function post-MI, relative to wild-type controls.[9] the mechanisms by which vitamin D may regulate cardiovascular function in MI are still controversial. FGF23 may contribute to left ventricular hypertrophy by a direct, Klotho-independent action on cardiomyocytes.[30]
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