5 results on '"Durham KK"'
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2. High Density Lipoprotein and Its Precursor Protein Apolipoprotein A1 as Potential Therapeutics to Prevent Anthracycline Associated Cardiotoxicity.
- Author
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Kluck GEG, Durham KK, Yoo JA, and Trigatti BL
- Abstract
Cardiovascular disease and cancer are the leading causes of death in developed societies. Despite their effectiveness, many cancer therapies exhibit deleterious cardiovascular side effects such as cardiotoxicity and heart failure. The cardiotoxic effects of anthracyclines such as doxorubicin are the most well-characterized of cardiotoxic anti-cancer therapies. While other anti-neoplastic drugs also induce cardiotoxicity, often leading to heart failure, they are beyond the scope of this review. This review first summarizes the mechanisms of doxorubicin-induced cardiotoxicity. It then reviews emerging preclinical evidence that high density lipoprotein and its precursor protein apolipoprotein A1, which are known for their protective effects against ischemic cardiovascular disease, may also protect against doxorubicin-induced cardiotoxicity both directly and indirectly, when used therapeutically., (Copyright © 2020 Kluck, Durham, Yoo and Trigatti.)
- Published
- 2020
- Full Text
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3. Treatment with apolipoprotein A1 protects mice against doxorubicin-induced cardiotoxicity in a scavenger receptor class B, type I-dependent manner.
- Author
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Durham KK, Kluck G, Mak KC, Deng YD, and Trigatti BL
- 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
- 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.
- Published
- 2019
- Full Text
- View/download PDF
4. High-density lipoprotein protects cardiomyocytes against necrosis induced by oxygen and glucose deprivation through SR-B1, PI3K, and AKT1 and 2.
- Author
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Durham KK, Chathely KM, and Trigatti BL
- Subjects
- Animals, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Necrosis, Phosphorylation, Signal Transduction, CD36 Antigens physiology, Glucose deficiency, Lipoproteins, HDL pharmacology, Myocytes, Cardiac drug effects, Oxygen toxicity, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism
- Abstract
The cardioprotective lipoprotein HDL (high-density lipoprotein) prevents myocardial infarction and cardiomyocyte death due to ischemia/reperfusion injury. The scavenger receptor class B, type 1 (SR-B1) is a high-affinity HDL receptor and has been shown to mediate HDL-dependent lipid transport as well as signaling in a variety of different cell types. The contribution of SR-B1 in cardiomyocytes to the protective effects of HDL on cardiomyocyte survival following ischemia has not yet been studied. Here, we use a model of simulated ischemia (oxygen and glucose deprivation, OGD) to assess the mechanistic involvement of SR-B1, PI3K (phosphatidylinositol-3-kinase), and AKT in HDL-mediated protection of cardiomyocytes from cell death. Neonatal mouse cardiomyocytes and immortalized human ventricular cardiomyocytes, subjected to OGD for 4 h, underwent substantial cell death due to necrosis but not necroptosis or apoptosis. Pretreatment of cells with HDL, but not low-density lipoprotein, protected them against OGD-induced necrosis. HDL-mediated protection was lost in cardiomyocytes from SR-B1
-/- mice or when SR-B1 was knocked down in human immortalized ventricular cardiomyocytes. HDL treatment induced the phosphorylation of AKT in cardiomyocytes in an SR-B1-dependent manner. Finally, chemical inhibition of PI3K or AKT or silencing of either AKT1 or AKT2 gene expression abolished HDL-mediated protection against OGD-induced necrosis of cardiomyocytes. These results are the first to identify a role of SR-B1 in mediating the protective effects of HDL against necrosis in cardiomyocytes, and to identify AKT activation downstream of SR-B1 in cardiomyocytes., (© 2018 The Author(s).)- Published
- 2018
- Full Text
- View/download PDF
5. HDL protects against doxorubicin-induced cardiotoxicity in a scavenger receptor class B type 1-, PI3K-, and Akt-dependent manner.
- Author
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Durham KK, Chathely KM, Mak KC, Momen A, Thomas CT, Zhao YY, MacDonald ME, Curtis JM, Husain M, and Trigatti BL
- Subjects
- Animals, Apolipoprotein A-I genetics, Apolipoprotein A-I metabolism, Apoptosis, Atrophy, Cardiomyopathies chemically induced, Cardiomyopathies enzymology, Cardiomyopathies physiopathology, Cardiotoxicity, Cell Line, Disease Models, Animal, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Myocytes, Cardiac pathology, Scavenger Receptors, Class B deficiency, Scavenger Receptors, Class B genetics, Signal Transduction, Ventricular Dysfunction, Left chemically induced, Ventricular Dysfunction, Left enzymology, Ventricular Dysfunction, Left physiopathology, Ventricular Function, Left, Cardiomyopathies prevention & control, Doxorubicin, Lipoproteins, HDL metabolism, Myocytes, Cardiac enzymology, Phosphatidylinositol 3-Kinase metabolism, Proto-Oncogene Proteins c-akt metabolism, Scavenger Receptors, Class B metabolism, Ventricular Dysfunction, Left prevention & control
- Abstract
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 (apoA1
Tg/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.- Published
- 2018
- Full Text
- View/download PDF
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