The vitamin D receptor activator paricalcitol prevents fibrosis and diastolic dysfunction in a murine model of pressure overload

BackgroundActivation of the vitamin D–vitamin D receptor (VDR) axis has been shown to reduce blood pressure and left ventricular (LV) hypertrophy. Besides cardiac hypertrophy, cardiac fibrosis is a key element of adverse cardiac remodeling. We hypothesized that activation of the VDR by paricalcitol would prevent fibrosis and LV diastolic dysfunction in an established murine model of cardiac remodeling.MethodsMice were subjected to transverse aortic constriction (TAC) to induce cardiac hypertrophy. Mice were treated with paricalcitol, losartan, or a combination of both for a period of four consecutive weeks.ResultsThe fixed aortic constriction caused similar increase in blood pressure, both in untreated and paricalcitol- or losartan-treated mice. TAC significantly increased LV weight compared to sham operated animals (10.2 ± 0.7 vs. 6.9 ± 0.3 mg/mm, p < 0.05). Administration of either paricalcitol (10.5 ± 0.7), losartan (10.8 ± 0.4), or a combination of both (9.2 ± 0.6) did not reduce LV weight. Fibrosis was significantly increased in mice undergoing TAC (5.9 ± 1.0 vs. sham 2.4 ± 0.8%, p < 0.05). Treatment with losartan and paricalcitol reduced fibrosis (paricalcitol 1.6 ± 0.3% and losartan 2.9 ± 0.6%, both p < 0.05 vs. TAC). This reduction in fibrosis in paricalcitol treated mice was associated with improved indices of LV contraction and relaxation, e.g. dPdtmax and dPdtmin and lower LV end diastolic pressure, and relaxation constant Tau. Also, treatment with paricalcitol and losartan reduced mRNA expression of ANP, fibronectin, collagen III and TIMP-1.DiscussionTreatment with the selective VDR activator paricalcitol reduces myocardial fibrosis and preserves diastolic LV function due to pressure overload in a mouse model. This is associated with a reduced percentage of fibrosis and a decreased expression of ANP and several other tissue markers.

► We evaluated the efficacy of the selective vitamin D receptor activator paricalcitol in a mouse model of pressure overload. ► Paricalcitol normalizes diastolic dysfunction, independent from blood pressure. ► This is associated with reduced cardiac fibrosis and lower expression of myocardial matrix proteins. ► Paricalcitol did not exert additional beneficial effects on top of the established heart failure drug losartan.