Back to Search
Start Over
Treatment with apolipoprotein A1 protects mice against doxorubicin-induced cardiotoxicity in a scavenger receptor class B, type I-dependent manner.
- Source :
-
American journal of physiology. Heart and circulatory physiology [Am J Physiol Heart Circ Physiol] 2019 Jun 01; Vol. 316 (6), pp. H1447-H1457. Date of Electronic Publication: 2019 Apr 19. - Publication Year :
- 2019
-
Abstract
- 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 KK, Chathely KM, Mak KC, Momen A, Thomas CT, Zhao YY, MacDonald ME, Curtis JM, Husain M, Trigatti BL. HDL protects against doxorubicin-induced cardiotoxicity in a scavenger receptor class B type 1-, phosphatidylinositol 3-kinase-, and Akt-dependent manner. Am J Physiol Heart Circ Physiol 314: H31-H44, 2018]. 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 preincubation 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. NEW & NOTEWORTHY We show that scavenger receptor class B, type I (SR-B1) mediates HDL-dependent protection against doxorubicin-induced cardiomyocyte apoptosis and that this is a property of SR-B1 in cardiomyocytes in vitro and in hearts in vivo. We also demonstrate that pharmacological treatment with apolipoprotein A1, the major HDL structural protein, protects mice against doxorubicin-induced cardiomyocyte apoptosis and left ventricular dysfunction in an SR-B1-dependent manner. This suggests that HDL-targeted pharmacological therapy may hold promise for protecting against the deleterious, cardiotoxic side effects of this commonly used chemotherapeutic drug.
- Subjects :
- Animals
Cardiomyopathies chemically induced
Cardiomyopathies metabolism
Cardiomyopathies pathology
Cytoprotection
Disease Models, Animal
Male
Mice, Inbred C57BL
Mice, Knockout
Myocytes, Cardiac metabolism
Myocytes, Cardiac pathology
Scavenger Receptors, Class B deficiency
Scavenger Receptors, Class B genetics
Signal Transduction
Ventricular Dysfunction, Left chemically induced
Ventricular Dysfunction, Left metabolism
Ventricular Dysfunction, Left physiopathology
Apolipoprotein A-I pharmacology
Apoptosis drug effects
Cardiomyopathies prevention & control
Doxorubicin
Myocytes, Cardiac drug effects
Scavenger Receptors, Class B metabolism
Ventricular Dysfunction, Left prevention & control
Ventricular Function, Left drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1539
- Volume :
- 316
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Heart and circulatory physiology
- Publication Type :
- Academic Journal
- Accession number :
- 31002281
- Full Text :
- https://doi.org/10.1152/ajpheart.00432.2018