Role of L-type Ca2+ channel and oxidative stress in the pathogenesis of iron-overload cardiomyopathy
Subtitle: calcium channel blockers and taurine as potential therapies.
Published: 2005
Language: eng
Number of pages: 174
Description: The prevalence of primary (hereditary) hemochromatosis and secondary iron overload (hemosiderosis) is reaching epidemic levels worldwide. Iron overload leads to excessive iron deposition in a wide variety of tissues, including the heart and endocrine tissues. Iron-overload cardiomyopathy is the primary determinant of survival in patients with secondary iron overload while being a leading cause of morbidity and mortality in patients with primary hemochromatosis. A marked gender difference exists in type 1 primary hemochromatosis with females having less cardiomyopathy and diabetes mellitus compared to males. Despite a clear connection between elevated iron levels and clinical disease, our understanding of iron transport remains incomplete.Radioactive iron uptake in rat Langendorff hearts was reduced by L-type Ca2+ channel (LTCC) blockers and potentiate by LTCC agonist. Iron overload in mice was associated with increased mortality, systolic and diastolic dysfunction, bradycardia, hypotension, increased myocardial fibrosis and elevated oxidative stress. Treatment with LTCC blockers (CCBs; amlodipine and verapamil) at therapeutic levels inhibited the LTCC current in cardiomyocytes, attenuated myocardial iron accumulation and oxidative stress, improved survival, prevented hypotension and preserved heart structure and function. Iron-overloaded transgenic mice with cardiac-specific overexpression of the LVDCC alpha1-subunit had twofold higher myocardial iron and oxidative stress levels, as well as greater impairment in cardiac function, compared with littermate controls; LTCC blockade was again protective. Consistent with the role of LTCCs in myocardial iron uptake, iron-overload female mice show better survival with lowered cardiac dysfunction and iron-induced oxidative stress. These results indicate that cardiac LTCCs are key transporters of iron into cardiomyocytes under iron-overloaded conditions. Given the high degree of iron-induced oxidative stress, we hypothesize that the antioxidant and endogenous LTCC blocker, taurine, may also exert protective effects in iron-overload cardiomyopathy. Taurine supplementation increases myocardial taurine levels and reduced iron-induced oxidative stress with a protection of myocardial glutathione levels. Consequently, LTCC blockers and/or taurine supplementation may represent a new therapeutic tool to reduce the toxic effects of excess iron including the cardiovascular burden from iron-overload.
Notes: Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5317.

Thesis (Ph.D.)--University of Toronto, 2005.

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