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. / published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/161524 |
| Date | January 2012 |
| Creators | Yang, Bo, 杨波 |
| Contributors | Wang, Y, Vanhoutte, PMGR, Xia, Z |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Source | http://hub.hku.hk/bib/B47869641 |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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