Thyroid hormone induces cyclin D1 nuclear translocation and DNA synthesis in adult rat cardiomyocytes.
Although mammalian cardiomyocytes lose their proliferative capacity after birth, there is evidence that postmitotic cardiomyocytes can proliferate provided that cyclin D1 accumulates in the nucleus. Here we show by Northern blot, Western analysis, and immunohistochemistry that 3,5,3'-triiodothyronine (T3) treatment of adult rats caused an increase of cyclin D1 mRNA and protein levels. The increased cyclin D1 protein content was associated with its translocation into the nucleus of cardiomyocytes. These changes were accompanied by the re-entry of cardiomyocytes into the cell cycle, as demonstrated by increased levels of cyclin A, PCNA, and incorporation of bromodeoxyuridine into DNA (labeling index was 30.2% in T3-treated rats vs. 2.2% in controls). Entry into the S phase was associated with an increased mitotic activity as demonstrated by positivity of cardiomyocyte nuclei to antibodies anti-phosphohistone-3, a specific marker of the mitotic phase (mitotic index was 3.01/1000 cardiomyocte nuclei in hyperthyroid rats vs. 0.04 in controls). No biochemical or histological signs of tissue damage were observed in the heart of T3-treated rats. These results demonstrated that T3 treatment is associated with a re-entry of cardiomyocytes into the cell cycle and so may be important for the development of future therapeutic strategies aimed at inducing proliferation of cardiomyocytes.
Ledda-Columbano
Giovanna M
GM
Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, Italy. gmledda@unica.it
Molotzu
Francesca
F
Pibiri
Monica
M
Cossu
Costanza
C
Perra
Andrea
A
Columbano
Amedeo
A
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D006332:Cardiomegaly / Q000139:chemically induced; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism*; D003402:Creatine Kinase / Q000097:blood; D003404:Creatinine / Q000097:blood; D019938:Cyclin D1 / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis*; D004261:DNA Replication / Q000187:drug effects*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014284:Triiodothyronine / Q000494:pharmacology*
D012333:RNA, Messenger; D014284:Triiodothyronine; D019938:Cyclin D1; D004247:DNA; D003404:Creatinine; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D001973:Bromodeoxyuridine