Vitamin D Pathway Activation Reduces Cardiomyocyte DNA Damage and Improves Cardiac Contractility in Preclinical Models.
BACKGROUND: In heart failure (HF), DNA damage caused by various external stressors contributes to cardiac dysfunction through the activation of DNA damage response pathways. To date, no clinical strategies have been established to restore cardiac function by reducing accumulated DNA damage. We previously found that vitamin D improved contractility in lamin A/C (LMNA) p.Q353R-mutant induced pluripotent stem (iPS) cell-derived cardiomyocytes (iPSCMs), but whether this effect extends to other LMNA variants and in vivo models remained uncertain. OBJECTIVES: The objective of the study was to evaluate the association of vitamin D pathway activation with cardiomyocyte phosphorylated histone H2AX (γH2AX) foci and contractile phenotypes in patient-derived iPSCMs and mouse models of HF. METHODS: iPS cell lines were generated from dilated cardiomyopathy patients carrying the LMNA p.R225X mutation, and the effects of vitamin D treatment on γH2AX foci and cardiomyocyte contractility were evaluated. In addition, the effects of the vitamin D analog paricalcitol were evaluated in Lmna p.R225X mice and in a pressure overload mouse model of HF. RESULTS: Consistent with previous findings, vitamin D treatment reduced γH2AX foci in cardiomyocytes derived from LMNA p.R225X mutant iPS cells through upregulating the expression of DNA repair factors, and improved contractility in these iPSCMs. Furthermore, paricalcitol reduced γH2AX foci and attenuated cardiac dysfunction in both Lmna p.R225X mice and pressure overload HF model mice. CONCLUSIONS: Vitamin D pathway activation improved contractile phenotypes across complementary preclinical models and was accompanied by reduced γH2AX foci or related transcriptional changes. These findings support further mechanistic and preclinical investigation.