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Postgraduate Thesis: Role of lipocalin-2 in cardiac dysfunction associated with aging and dietary obesity
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TitleRole of lipocalin-2 in cardiac dysfunction associated with aging and dietary obesity
 
AuthorsYang, Bo
杨波
 
Issue Date2012
 
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
 
AbstractObesity is closely related to many medical complications such as type 2 diabetes, hypertension and heart failure. Obesity and other factors, including elevated blood glucose levels, hypertension, and dyslipidemia, constitute a constellation of symptoms known as the metabolic syndrome, which are the risk factors for coronary artery disease. Lipocalin-2 is a pro-inflammatory adipokine causally involved in the development of obesity-associated metabolic and cardiovascular diseases. Recent clinical and experimental evidences demonstrate an association between augmented circulating lipocalin-2 and cardiac dysfunction. However, little is known about the detailed roles of lipocalin-2 in regulating pathophysiological functions of the heart. The present study was designed to compare the heart functions of mice with normal (WT) or deficient lipocalin-2 (Lcn2-KO) expression and to examine the molecular mechanisms underlying lipocalin-2-mediated deteriorated effects in hearts. Echocardiographic analysis revealed that the myocardial contractile function was significantly improved in hearts of Lcn2-KO mice, under both standard chow and high fat diet conditions. The heart function before and after I/R injury (20-min of global ischemia followed by 60-min of reperfusion) was assessed using the Langendorff perfusion system. Compared with WT littermates, hearts from Lcn2-KO mice showed improved functional recovery and reduced infarct size following I/R. These phenomena can be observed in mice under both standard chow and high fat feeding conditions. Under baseline condition, the mitochondrial function of hearts from Lcn2-KO mice was significantly enhanced, as demonstrated by biochemical analysis of respiratory chain activity, markers of biogenesis and oxidative stress, as well as electron microscopic investigation of the mitochondrial ultrastructure. Acute or chronic administration of lipocalin-2 impaired cardiac functional recovery to I/R and dampened the mitochondrial function in hearts of Lcn2-KO mice. These effects were associated with an extensive modification of the fatty acyl chain compositions of intracellular phospholipids. In particular, lipocalin-2 facilitated the redistribution of linoleic acid (C18:2) among different types of phospholipid, including cardiolipin, which is exclusively located in the mitochondria inner membrane. The direct effects of lipocalin-2 on both H9c2 and NCM cells were also examined. TUNEL assay and flow cytometry analysis demonstrated that lipocalin-2 treatment promoted apoptosis in cardiomyocytes. Lipocalin-2 induced an early phase of phosphatidylserine exposure, followed by Bax-translocation and caspase-3 cleavage. The results collectively suggested that lipocalin-2 initiated the intrinsic mitochondria-mediated apoptotic pathway. In the hearts of Lcn2-KO mice, significantly reduced number of apoptotic cells was observed after I/R injury. In conclusion, lacking of lipocalin-2 improved heart function recovery during I/R injury via mitochondrial function restoration, phospholipids remodeling, and inhibition of cardiomyocytes apoptosis.
 
AdvisorsWang, Y
Vanhoutte, PMGR
Xia, Z
 
DegreeDoctor of Philosophy
 
SubjectGlycoproteins.
Aging.
Obesity - Complications.
Cardiovascular system - Diseases.
 
Dept/ProgramPharmacology and Pharmacy
 
DC FieldValue
dc.contributor.advisorWang, Y
 
dc.contributor.advisorVanhoutte, PMGR
 
dc.contributor.advisorXia, Z
 
dc.contributor.authorYang, Bo
 
dc.contributor.author杨波
 
dc.date.hkucongregation2012
 
dc.date.issued2012
 
dc.description.abstractObesity is closely related to many medical complications such as type 2 diabetes, hypertension and heart failure. Obesity and other factors, including elevated blood glucose levels, hypertension, and dyslipidemia, constitute a constellation of symptoms known as the metabolic syndrome, which are the risk factors for coronary artery disease. Lipocalin-2 is a pro-inflammatory adipokine causally involved in the development of obesity-associated metabolic and cardiovascular diseases. Recent clinical and experimental evidences demonstrate an association between augmented circulating lipocalin-2 and cardiac dysfunction. However, little is known about the detailed roles of lipocalin-2 in regulating pathophysiological functions of the heart. The present study was designed to compare the heart functions of mice with normal (WT) or deficient lipocalin-2 (Lcn2-KO) expression and to examine the molecular mechanisms underlying lipocalin-2-mediated deteriorated effects in hearts. Echocardiographic analysis revealed that the myocardial contractile function was significantly improved in hearts of Lcn2-KO mice, under both standard chow and high fat diet conditions. The heart function before and after I/R injury (20-min of global ischemia followed by 60-min of reperfusion) was assessed using the Langendorff perfusion system. Compared with WT littermates, hearts from Lcn2-KO mice showed improved functional recovery and reduced infarct size following I/R. These phenomena can be observed in mice under both standard chow and high fat feeding conditions. Under baseline condition, the mitochondrial function of hearts from Lcn2-KO mice was significantly enhanced, as demonstrated by biochemical analysis of respiratory chain activity, markers of biogenesis and oxidative stress, as well as electron microscopic investigation of the mitochondrial ultrastructure. Acute or chronic administration of lipocalin-2 impaired cardiac functional recovery to I/R and dampened the mitochondrial function in hearts of Lcn2-KO mice. These effects were associated with an extensive modification of the fatty acyl chain compositions of intracellular phospholipids. In particular, lipocalin-2 facilitated the redistribution of linoleic acid (C18:2) among different types of phospholipid, including cardiolipin, which is exclusively located in the mitochondria inner membrane. The direct effects of lipocalin-2 on both H9c2 and NCM cells were also examined. TUNEL assay and flow cytometry analysis demonstrated that lipocalin-2 treatment promoted apoptosis in cardiomyocytes. Lipocalin-2 induced an early phase of phosphatidylserine exposure, followed by Bax-translocation and caspase-3 cleavage. The results collectively suggested that lipocalin-2 initiated the intrinsic mitochondria-mediated apoptotic pathway. In the hearts of Lcn2-KO mice, significantly reduced number of apoptotic cells was observed after I/R injury. In conclusion, lacking of lipocalin-2 improved heart function recovery during I/R injury via mitochondrial function restoration, phospholipids remodeling, and inhibition of cardiomyocytes apoptosis.
 
dc.description.naturepublished_or_final_version
 
dc.description.thesisdisciplinePharmacology and Pharmacy
 
dc.description.thesisleveldoctoral
 
dc.description.thesisnameDoctor of Philosophy
 
dc.identifier.hkulb4786964
 
dc.languageeng
 
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)
 
dc.relation.ispartofHKU Theses Online (HKUTO)
 
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
dc.source.urihttp://hub.hku.hk/bib/B47869641
 
dc.subject.lcshGlycoproteins.
 
dc.subject.lcshAging.
 
dc.subject.lcshObesity - Complications.
 
dc.subject.lcshCardiovascular system - Diseases.
 
dc.titleRole of lipocalin-2 in cardiac dysfunction associated with aging and dietary obesity
 
dc.typePG_Thesis
 
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<item><contributor.advisor>Wang, Y</contributor.advisor>
<contributor.advisor>Vanhoutte, PMGR</contributor.advisor>
<contributor.advisor>Xia, Z</contributor.advisor>
<contributor.author>Yang, Bo</contributor.author>
<contributor.author>&#26472;&#27874;</contributor.author>
<date.issued>2012</date.issued>
<description.abstract>&#65279;Obesity is closely related to many medical complications such as type 2 diabetes,

hypertension and heart failure. Obesity and other factors, including elevated blood

glucose levels, hypertension, and dyslipidemia, constitute a constellation of symptoms

known as the metabolic syndrome, which are the risk factors for coronary artery

disease. Lipocalin-2 is a pro-inflammatory adipokine causally involved in the

development of obesity-associated metabolic and cardiovascular diseases. Recent

clinical and experimental evidences demonstrate an association between augmented

circulating lipocalin-2 and cardiac dysfunction. However, little is known about the

detailed roles of lipocalin-2 in regulating pathophysiological functions of the heart.

The present study was designed to compare the heart functions of mice with normal

(WT) or deficient lipocalin-2 (Lcn2-KO) expression and to examine the molecular

mechanisms underlying lipocalin-2-mediated deteriorated effects in hearts.

Echocardiographic analysis revealed that the myocardial contractile function was

significantly improved in hearts of Lcn2-KO mice, under both standard chow and

high fat diet conditions. The heart function before and after I/R injury (20-min of

global ischemia followed by 60-min of reperfusion) was assessed using the

Langendorff perfusion system. Compared with WT littermates, hearts from Lcn2-KO

mice showed improved functional recovery and reduced infarct size following I/R.

These phenomena can be observed in mice under both standard chow and high fat

feeding conditions.

Under baseline condition, the mitochondrial function of hearts from Lcn2-KO

mice was significantly enhanced, as demonstrated by biochemical analysis of

respiratory chain activity, markers of biogenesis and oxidative stress, as well as

electron microscopic investigation of the mitochondrial ultrastructure. Acute or

chronic administration of lipocalin-2 impaired cardiac functional recovery to I/R and

dampened the mitochondrial function in hearts of Lcn2-KO mice. These effects were

associated with an extensive modification of the fatty acyl chain compositions of

intracellular phospholipids. In particular, lipocalin-2 facilitated the redistribution of

linoleic acid (C18:2) among different types of phospholipid, including cardiolipin,

which is exclusively located in the mitochondria inner membrane.

The direct effects of lipocalin-2 on both H9c2 and NCM cells were also

examined. TUNEL assay and flow cytometry analysis demonstrated that lipocalin-2

treatment promoted apoptosis in cardiomyocytes. Lipocalin-2 induced an early phase

of phosphatidylserine exposure, followed by Bax-translocation and caspase-3

cleavage. The results collectively suggested that lipocalin-2 initiated the intrinsic

mitochondria-mediated apoptotic pathway. In the hearts of Lcn2-KO mice,

significantly reduced number of apoptotic cells was observed after I/R injury.

In conclusion, lacking of lipocalin-2 improved heart function recovery during I/R

injury via mitochondrial function restoration, phospholipids remodeling, and

inhibition of cardiomyocytes apoptosis.</description.abstract>
<language>eng</language>
<publisher>The University of Hong Kong (Pokfulam, Hong Kong)</publisher>
<relation.ispartof>HKU Theses Online (HKUTO)</relation.ispartof>
<rights>The author retains all proprietary rights, (such as patent rights) and the right to use in future works.</rights>
<rights>Creative Commons: Attribution 3.0 Hong Kong License</rights>
<source.uri>http://hub.hku.hk/bib/B47869641</source.uri>
<subject.lcsh>Glycoproteins.</subject.lcsh>
<subject.lcsh>Aging.</subject.lcsh>
<subject.lcsh>Obesity - Complications.</subject.lcsh>
<subject.lcsh>Cardiovascular system - Diseases.</subject.lcsh>
<title>Role of lipocalin-2 in cardiac dysfunction associated with aging and dietary obesity</title>
<type>PG_Thesis</type>
<identifier.hkul>b4786964</identifier.hkul>
<description.thesisname>Doctor of Philosophy</description.thesisname>
<description.thesislevel>doctoral</description.thesislevel>
<description.thesisdiscipline>Pharmacology and Pharmacy</description.thesisdiscipline>
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<date.hkucongregation>2012</date.hkucongregation>
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