Defective Extracellular Pyrophosphate Metabolism Promotes Vascular Calcification in a Mouse Model of Hutchinson-Gilford Progeria Syndrome that is Ameliorated upon Pyrophosphate Treatment
Background—Progerin is a mutant form of lamin A responsible for Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder characterized by excessive atherosclerosis and vascular calcification that leads to premature death, predominantly from myocardial infarction or stroke. The goal of this study was to investigate mechanisms causing excessive vascular calcification in HGPS.
Methods and Results—We performed expression and functional studies in wild-type mice and knock-in LmnaG609G/+ mice expressing progerin, which mimic the main clinical manifestations of HGPS. LmnaG609G/+ mice showed excessive aortic calcification, and primary aortic vascular smooth muscle cells (VSMCs) from these progeroid animals have an impaired capacity to inhibit vascular calcification. This defect in progerin-expressing VSMCs is associated with increased tissue expression and activity of tissue-nonspecific alkaline phosphatase (TNAP) and mitochondrial dysfunction leading to reduced ATP synthesis. Accordingly, LmnaG609G/+ VSMCs are defective for the production and extracellular accumulation of pyrophosphate, a major inhibitor of vascular calcification. We also found increased alkaline phosphatase activity and reduced ATP and pyrophosphate levels in plasma of LmnaG609G/+ mice without changes in phosphorus and calcium. Treatment with pyrophosphate inhibited vascular calcification in progeroid mice.
Conclusions—Excessive vascular calcification in LmnaG609G mice is caused by reduced extracellular accumulation of pyrophosphate resulting from increased TNAP activity and diminished ATP availability caused by mitochondrial dysfunction in VSMCs. Excessive calcification is ameliorated upon pyrophosphate treatment. These findings reveal a previously undefined pathogenic process in HGPS that may also contribute to vascular calcification in normal aging, since progerin progressively accumulates in the vascular tissue of non-HGPS individuals.
- Hutchinson-Gilford progeria syndrome
- basic science
- lamin A/C
- smooth muscle cell
- vascular calcification
- Received December 11, 2012.
- Revision received March 26, 2013.
- Accepted April 17, 2013.