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

Abstract

BACKGROUND:

Activation 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.

METHODS:

Mice 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.

RESULTS:

The 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.

DISCUSSION:

Treatment 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.

• Authors: Laura M G Meems, Megan V Cannon, Hasan Mahmud, Adriaan A Voors, Wiek H van Gilst, Herman H W Silljé, Willem P T Ruifrok, Rudolf A de Boer
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 132 Issue 3-5 Pg. 282-9 (Nov 2012) ISSN: 1879-1220 [Electronic] England
• PMID: 22800987 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Collagen Type III
• Ergocalciferols
• Fibronectins
• Tissue Inhibitor of Metalloproteinase-1
• paricalcitol
• Atrial Natriuretic Factor
• Losartan

Topics

• Animals
• Aorta (drug effects)
• Atrial Natriuretic Factor (genetics)
• Blood Pressure (drug effects)
• Collagen Type III (genetics)
• Disease Models, Animal
• Ergocalciferols (pharmacology)
• Fibronectins (genetics)
• Fibrosis (prevention & control)
• Gene Expression Regulation (drug effects)
• Hypertrophy, Left Ventricular (drug therapy, etiology, pathology)
• Losartan (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Myocardium (pathology)
• Tissue Inhibitor of Metalloproteinase-1 (genetics)
• Ventricular Function, Left (drug effects)
• Ventricular Pressure
• Ventricular Remodeling (drug effects)