HDL protects against doxorubicin-induced cardiotoxicity in a scavenger receptor class B type 1-, PI3K-, and Akt-dependent manner

Am J Physiol Heart Circ Physiol. 2018 Jan 1;314(1):H31-H44. doi: 10.1152/ajpheart.00521.2016. Epub 2017 Oct 6.


Doxorubicin is a widely used chemotherapeutic with deleterious cardiotoxic side effects. HDL has been shown to protect cardiomyocytes in vitro against doxorubicin-induced apoptosis. Scavenger receptor class B type 1 (SR-B1), a high-affinity HDL receptor, mediates cytoprotective signaling by HDL through Akt. Here, we assessed whether increased HDL levels protect against doxorubicin-induced cardiotoxicity in vivo and in cardiomyocytes in culture and explored the intracellular signaling mechanisms involved, particularly the role of SR-B1. Transgenic mice with increased HDL levels through overexpression of human apolipoprotein A1 (apoA1Tg/Tg) and wild-type mice (apoA1+/+) with normal HDL levels were treated repeatedly with doxorubicin. After treatment, apoA1+/+ mice displayed cardiac dysfunction, as evidenced by reduced left ventricular end-systolic pressure and +dP/d t, and histological analysis revealed cardiomyocyte atrophy and increased cardiomyocyte apoptosis after doxorubicin treatment. In contrast, apoA1Tg/Tg mice were protected against doxorubicin-induced cardiac dysfunction and cardiomyocyte atrophy and apoptosis. When SR-B1 was knocked out, however, overexpression of apoA1 did not protect against doxorubicin-induced cardiotoxicity. Using primary neonatal mouse cardiomyocytes and human immortalized ventricular cardiomyocytes in combination with genetic knockout, inhibitors, or siRNA-mediated knockdown, we demonstrated that SR-B1 is required for HDL-mediated protection of cardiomyocytes against doxorubicin-induced apoptosis in vitro via a pathway involving phosphatidylinositol 3-kinase and Akt1/2. Our findings provide proof of concept that raising apoA1 to supraphysiological levels can dramatically protect against doxorubicin-induced cardiotoxicity via a pathway that is mediated by SR-B1 and involves Akt1/2 activation in cardiomyocytes. NEW & NOTEWORTHY We have identified an important role for the scavenger receptor class B type 1 in facilitating high-density lipoprotein-mediated protection of cardiomyocytes against stress-induced apoptosis and shown that increasing plasma high-density lipoprotein protects against the deleterious side effects of the chemotherapeutic and cardiotoxic drug doxorubicin.

Keywords: cardiomyocyte; cardiotoxicity; doxorubicin; high-density lipoprotein; phosphatidylinositol 3-kinase; scavenger receptor class B type 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoprotein A-I / genetics
  • Apolipoprotein A-I / metabolism
  • Apoptosis
  • Atrophy
  • Cardiomyopathies / chemically induced
  • Cardiomyopathies / enzymology
  • Cardiomyopathies / physiopathology
  • Cardiomyopathies / prevention & control*
  • Cardiotoxicity
  • Cell Line
  • Disease Models, Animal
  • Doxorubicin*
  • Humans
  • Lipoproteins, HDL / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Scavenger Receptors, Class B / deficiency
  • Scavenger Receptors, Class B / genetics
  • Scavenger Receptors, Class B / metabolism*
  • Signal Transduction
  • Ventricular Dysfunction, Left / chemically induced
  • Ventricular Dysfunction, Left / enzymology
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Dysfunction, Left / prevention & control*
  • Ventricular Function, Left


  • APOA1 protein, human
  • Apolipoprotein A-I
  • Lipoproteins, HDL
  • Scarb1 protein, mouse
  • Scavenger Receptors, Class B
  • Doxorubicin
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt