Lack of vitamin D signalling per se does not aggravate cardiac functional impairment induced by myocardial infarction in mice

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.

Vitamin D Stimulates Cardiomyocyte Proliferation and Controls Organ Size and Regeneration in Zebrafish

“…Stimulation of heart regeneration in mammals by secreted factors may be more complex than in zebrafish, as mammalian adult CMs have a lower proliferative capacity and/or more hurdles to division like polyploidy (Gonzalez-Rosa et al, 2018;Patterson et al, 2017). Vitamin D signaling has been reported to protect mouse CMs from pathological hypertrophy by regulation of calcium handling (Chen et al, 2011;Choudhury et al, 2014;Ford et al, 2018), but we have identified no clear evidence from published literature for hyperplastic effects in mammalian hearts. To examine potential effects on cultured mouse P7 CMs, we treated with different concentrations of calcitriol and examined the expression of the proliferation marker Ki67 after 3 days.…”

Vitamin D and Cardiovascular Disease, with Emphasis on Hypertension, Atherosclerosis, and Heart Failure

“…Bae and coworkers reported detrimental effects of global VDR deficiency after experimental MI induced by permanent ligation of the left descending coronary artery in global VDR knock-out mice fed a normal diet [ 72 ]. By contrast, cardiac function after experimental MI was not different between normocalcemic VDR mutant mice on the rescue diet and wild-type mice [ 73 ]. Therefore, the detrimental effects of global VDR deficiency in MI mice may be attributed to hypocalcemia and secondary hyperparathyroidism [ 73 ].…”

“…By contrast, cardiac function after experimental MI was not different between normocalcemic VDR mutant mice on the rescue diet and wild-type mice [ 73 ]. Therefore, the detrimental effects of global VDR deficiency in MI mice may be attributed to hypocalcemia and secondary hyperparathyroidism [ 73 ].…”

Ablation of Vitamin D Signaling in Cardiomyocytes Leads to Functional Impairment and Stimulation of Pro-Inflammatory and Pro-Fibrotic Gene Regulatory Networks in a Left Ventricular Hypertrophy Model in Mice

“…In contrast, we observed no difference in the hypertrophic response of wild-type (WT) mice and those lacking VDR globally subjected to transverse aortic constriction (TAC), a standard model of experimental LVH induced by chronically increased afterload [22]. In addition, we found no difference in heart function between WT mice and global VDR knockout mice after myocardial infarction in an earlier study [23].…”