The transforming growth factor-Beta signaling pathway involvement in cardiovascular lesions in mucopolysaccharidosis-I.

Mucopolysaccharidoses (MPS) are a group of genetic disorders due to deficiency of lysosomal enzymes resulting in impaired glycosaminoglycan metabolism. All types of MPS can present with cardiovascular manifestation, although MPS-I, II, and VI seem to have more severe involvement than the other types. Enzyme replacement therapy (ERT) is available for MPS-I, II, and VI. Cardiovascular changes including hypertrophic cardiomyopathy, thickened valvular lesions, and coronary artery lesions often poorly respond to ERT and are well known as leading causes of death in patients with MPS-I. The mechanisms to cause these changes in MPS-I have not been well characterized. Immunohistopathological studies were conducted on the cardiac specimens from a patient with MPS-I who died due to sudden cardiac failure. Phosphorylated Smad2 staining showed hyperactive transforming growth factor-beta (TGF-β) signals in the intimal layer with myointimal proliferation causing stenosis in the coronary arteries as well as in the thickened endocardium and in the myocardial cells. TGF-β is involved in the pathogenesis of cardiovascular diseases including hypertrophic cardiomyopathy and vascular atherosclerosis. The primary mechanisms to cause hyperactive TGF-β signals in MPS-I are unknown. The similar mechanisms leading to hyperactive TGF-β signals may exist in the other types of MPS. The findings of TGF-β hyperactivity in the cardiovascular lesions in a patient with MPS-I may lead to a new therapeutic approach. Further studies are warranted to evaluate the effectiveness of the medications that suppress TGF-β signals, such as losartan, in preventing or improving cardiaovascular lesions in patients with MPS.