title: Increased oxidative stress contributes to cardiomyocyte dysfunction and death in patients with Fabry disease cardiomyopathy.
abstract: Cardiac dysfunction of Fabry disease (FD) has been associated with myofilament damage and cell death as result of α-galactosidase A deficiency and globotriaosylceramide accumulation. We sought to evaluate the role of oxidative stress in FD cardiomyocyte dysfunction. Myocardial tissue from 18 patients with FD was investigated for the expression of inducible nitric oxide synthase (iNOS) and nitrotyrosine by immunohistochemistry. Western blot analysis for nitrotyrosine was also performed. Oxidative damage to DNA was investigated by immunostaining for 8-hydroxydeoxyguanosine (8-OHdG), whereas apoptosis was evaluated by in situ ligation with hairpin probes. iNOS and nitrotyrosine expression was increased in FD hearts compared with hypertrophic cardiomyopathy and normal controls. Remarkably, immunostaining was homogeneously expressed in FD male cardiomyocytes, whereas it was only detected in the affected cardiomyocytes of FD females. Western blot analysis confirmed an increase in FD cardiomyocyte protein nitration compared with controls. 8-OHdG was expressed in 25% of cardiomyocyte nuclei from FD patients, whereas it was absent in controls. The intensity of immunostaining for iNOS/nitrotyrosine correlated with 8-OHdG expression in cardiomyocyte nuclei. Apoptosis of FD cardiomyocytes was 187-fold higher than in controls, and apoptotic nuclei were positive for 8-OHdG. Cardiac dysfunction of FD reflects increased myocardial nitric oxide production with oxidative damage of cardiomyocyte myofilaments and DNA, causing cell dysfunction and death.
authors.affiliation: Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences Department, La Sapienza University, Rome, Italy 00166; IRCCS L. Spallanzani, Rome, Italy 00149.
authors.forename: Cristina
authors.initials: C
authors.lastname: Chimenti
authors.affiliation: Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences Department, La Sapienza University, Rome, Italy 00166.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Scopelliti
authors.affiliation: IRCCS L. Spallanzani, Rome, Italy 00149.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Vulpis
authors.affiliation: Experimental Medicine and Pathology Department, La Sapienza University, Rome, Italy 00166.
authors.forename: Marco
authors.initials: M
authors.lastname: Tafani
authors.affiliation: Experimental Medicine and Pathology Department, La Sapienza University, Rome, Italy 00166.
authors.forename: Lidia
authors.initials: L
authors.lastname: Villanova
authors.affiliation: IRCCS L. Spallanzani, Rome, Italy 00149.
authors.forename: Romina
authors.initials: R
authors.lastname: Verardo
authors.affiliation: Department of Cardiac Surgery, European Hospital, Rome, Italy 00149.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Paulis
authors.affiliation: IRCCS S. Raffaele La Pisana, Rome, Italy 00163.
authors.forename: Matteo A
authors.initials: MA
authors.lastname: Russo
authors.affiliation: Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences Department, La Sapienza University, Rome, Italy 00166; IRCCS L. Spallanzani, Rome, Italy 00149. Electronic address: biocard@inmi.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Frustaci
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000502:physiology; D000795:Fabry Disease / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II
keywords: Cardiac dysfunction; Cardiomyopathy; Cell death; Fabry disease; Oxidative stress