Role of lipocalin-2 in cardiac dysfunction associated with aging and dietary obesity

Abstract

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.