Am J Physiol Heart Circ Physiol 2019 Apr 19. Epub 2019 Apr 19.
Biochemistry and Biomedical Sciences; and Thrombosis and Atherosclerosis Research Institute, McMaster University, Canada.
Doxorubicin, an agent used to treat a variety of cancers, is cardiotoxic by triggering cardiomyocyte apoptosis. We previously showed that treating cultured cardiomyocytes with human high density lipoprotein in vitro or transgenic overexpression of human apolipoprotein A1, its main structural protein protects against doxorubicin induced cardiomyocyte apoptosis in a manner dependent on the scavenger receptor class B type I [Durham (2018) 314: H31-H44]. This was due to high density lipoprotein induced activation of Akt signaling in cardiomyocytes. We now demonstrate that mice lacking the scavenger receptor class B type I exhibit increased sensitivity to doxorubicin-induced cardiomyocyte apoptosis in vivo. Cardiomyocytes expressing scavenger receptor class B type I are protected from doxorubicin-induced apoptosis by pre-incubation with high density lipoprotein isolated from wild type mice, whereas high density lipoprotein from scavenger receptor class B type 1 knockout mice is less effective. Cardiomyocytes from scavenger receptor class B type I knockout mice, however, are not protected by high density lipoprotein in vitro and hearts from knockout mice are more sensitive to doxorubicin in vivo. Pharmacological administration of purified apolipoprotein A1 dramatically protected wild type mice from doxorubicin-induced cardiotoxicity and left ventricular dysfunction, whereas this protection was lost in scavenger receptor class B type I-deficient mice. This demonstrates, at least in mice, that high density lipoprotein therapy can confer protection against doxorubicin-induced cardiomyocyte apoptosis in a manner mediated by the scavenger receptor class B type I.