Cardiac Expression of Neutrophil Gelatinase-Associated Lipocalin in a Model of Cancer Cachexia-Induced Cardiomyopathy

ESC Heart Fail. 2019 Feb;6(1):89-97. doi: 10.1002/ehf2.12372. Epub 2018 Oct 26.

Abstract

Aims: Cachexia is a severe consequence of cancer. Although cancer-induced heart atrophy leads to cardiac dysfunction and heart failure (HF), biomarkers for their diagnosis have not been identified. Neutrophil gelatinase-associated lipocalin (NGAL) is an aldosterone-responsive gene increased in HF. We studied NGAL and its association with aldosterone levels in a model of cancer cachexia-induced cardiomyopathy.

Methods and results: Rats were injected with Yoshida 108 AH-130 hepatoma cells to induce tumour. Cachectic rats were treated daily, for 16 days, with placebo or with 5 or 50 mg/kg/day of spironolactone. Cardiac function was analysed by echocardiography at baseline and at Day 11. Weight loss and atrophy of lean body and fat mass of cachectic rats were significantly attenuated by spironolactone. Cardiac dysfunction of tumour-bearing rats was improved by spironolactone. Plasma aldosterone was up-regulated from 337 ± 7 pg/mL in sham animals to 591 ± 31 pg/mL in the cachectic rats (P < 0.001 vs. sham). Treatment with 50 or 5 mg/kg/day of spironolactone reduced plasma aldosterone to 396 ± 22 and 391 ± 25 pg/mL (P < 0.01 vs. placebo). Plasma levels of NGAL were also increased in cachectic rats (1.462 ± 0.3603 μg/mL) than in controls (0.0936 ± 6 μg/mL, P < 0.001). Spironolactone treatment (50 mg/kg/day) significantly reduced cardiac mRNA and protein NGAL levels (P < 0.05 and P < 0.001 vs. placebo, respectively). NGAL mRNA and protein levels were overexpressed in cachectic animal hearts treated with placebo, compared with control (P < 0.05 and P < 0.01 vs. sham). Spironolactone treatment at 50 mg/kg/day reduced significantly cardiac NGAL (P < 0.05 and P < 0.001 vs. placebo).

Conclusions: Cancer cachexia induced increased levels of aldosterone and NGAL, contributing to worsening cardiac damage in cancer cachexia-induced cardiomyopathy. Spironolactone treatment may greatly attenuate cardiac dysfunction and lean mass atrophy associated with cancer cachexia.

Keywords: Aldosterone; Cancer cachexia; Cardiac wasting; Heart failure; Mineralcorticoid receptor; Neutrophil Gelatinase-Associated Lipocalin (NGAL); Spironolactone.

Publication types

  • Clinical Trial, Veterinary
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Proteins / biosynthesis
  • Acute-Phase Proteins / genetics*
  • Animals
  • Blotting, Western
  • Cachexia / complications*
  • Cachexia / metabolism
  • Cardiomyopathies / etiology
  • Cardiomyopathies / genetics*
  • Cardiomyopathies / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Lipocalins / biosynthesis
  • Lipocalins / genetics*
  • Male
  • Myocardium / metabolism*
  • Neoplasms, Experimental*
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / genetics*
  • RNA, Neoplasm / genetics
  • Random Allocation
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Acute-Phase Proteins
  • Lcn2 protein, rat
  • Lipocalins
  • Proto-Oncogene Proteins
  • RNA, Neoplasm