The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress.
Autophagy, an evolutionarily conserved process for the bulk degradation of cytoplasmic components, serves as a cell survival mechanism in starving cells. Although altered autophagy has been observed in various heart diseases, including cardiac hypertrophy and heart failure, it remains unclear whether autophagy plays a beneficial or detrimental role in the heart. Here, we report that the cardiac-specific loss of autophagy causes cardiomyopathy in mice. In adult mice, temporally controlled cardiac-specific deficiency of Atg5 (autophagy-related 5), a protein required for autophagy, led to cardiac hypertrophy, left ventricular dilatation and contractile dysfunction, accompanied by increased levels of ubiquitination. Furthermore, Atg5-deficient hearts showed disorganized sarcomere structure and mitochondrial misalignment and aggregation. On the other hand, cardiac-specific deficiency of Atg5 early in cardiogenesis showed no such cardiac phenotypes under baseline conditions, but developed cardiac dysfunction and left ventricular dilatation one week after treatment with pressure overload. These results indicate that constitutive autophagy in the heart under baseline conditions is a homeostatic mechanism for maintaining cardiomyocyte size and global cardiac structure and function, and that upregulation of autophagy in failing hearts is an adaptive response for protecting cells from hemodynamic stress.
Nakai
Atsuko
A
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita Osaka 565-0871, Japan.
Yamaguchi
Osamu
O
Takeda
Toshihiro
T
Higuchi
Yoshiharu
Y
Hikoso
Shungo
S
Taniike
Masayuki
M
Omiya
Shigemiki
S
Mizote
Isamu
I
Matsumura
Yasushi
Y
Asahi
Michio
M
Nishida
Kazuhiko
K
Hori
Masatsugu
M
Mizushima
Noboru
N
Otsu
Kinya
K
D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D001835:Body Weight; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology; D004452:Echocardiography; D006321:Heart / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics; D032342:Muscle Cells / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology
C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D013629:Tamoxifen