Abstract
Epidemiological studies have linked vitamin D deficiency to an increased incidence of myocardial infarction and support a role for vitamin D signalling in the pathophysiology of myocardial infarction. Vitamin D deficiency results in the development of secondary hyperparathyroidism, however, the role of secondary hyperparathyroidism in the pathophysiology of myocardial infarction is not known. Here, we aimed to explore further the secondary hyperparathyroidism independent role of vitamin D signalling in the pathophysiology of myocardial infarction by inducing experimental myocardial infarction in 3-month-old, male, wild-type mice and in mice lacking a functioning vitamin D receptor. In order to prevent secondary hyperparathyroidism in vitamin D receptor mutant mice, all mice were maintained on a rescue diet enriched with calcium, phosphorus, and lactose. Surprisingly, survival rate, cardiac function as measured by echocardiography and intra-cardiac catheterisation and cardiomyocyte size were indistinguishable between normocalcaemic vitamin D receptor mutant mice and wild-type controls, 2 and 8 weeks post-myocardial infarction. In addition, the myocardial infarction-induced inflammatory response was similar in vitamin D receptor mutants and wild-type mice, as evidenced by a comparable upregulation in cardiac interleukin-1-β and tumor-necrosis-factor-α mRNA abundance and similar elevations in circulating interleukin-1-β and tumor-necrosis-factor-α. Our data suggest that the lack of vitamin D signalling in normocalcaemic vitamin D receptor mutants has no major detrimental effect on cardiac function and outcome post-myocardial infarction. Our study may have important clinical implications because it suggests that the secondary hyperparathyroidism induced by vitamin D deficiency, rather than the lack of vitamin D signalling per se, may negatively impact cardiac function post-myocardial infarction.
Highlights
We found that vitamin D signalling regulates endothelial function by modulating the bioavailability of the vasodilator nitric oxide (NO) through the transcriptional control of endothelial-derived NO synthase [19]; a finding which was later confirmed in mice with endothelial cell specific vitamin D receptor (VDR) deletion [20]
Serum intact parathyroid hormone (PTH) levels tended to be non-significantly elevated in VDR mutant mice (Fig 1B), both sham and myocardial infarction (MI) VDR mutants on rescue diet were normocalcaemic, normophosphatemic, and normonatremic, and showed unchanged serum aldosterone levels compared with WT sham and MI mice (Fig 1A–1C, Table 1)
Vitamin D plays a critical role in mineral homeostasis, bone biology, immunity [51,52,53,54] and has been implicated in the pathophysiology of cardiovascular diseases (CVD)
Summary
A large Mendelian randomisation study failed to confirm the association between vitamin D status and CVD [7]. Intervention studies have provided conflicting evidence regarding the role of vitamin D in CVD therapy. While some studies support a cardioprotective role for vitamin D supplementation with active vitamin D analogues in both experimental MI models and in clinical studies [8,9,10], other studies failed to provide evidence for any beneficial therapeutic effect of vitamin D supplementation or active vitamin D analogues on vascular function and CVD outcome [11,12,13]. A recent review by Milazzo et al focusing on acute MI (AMI) and vitamin D, highlighted the necessity for well designed, adequately powered interventional trials to confirm the role of vitamin D in AMI patients [14]
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