Increased 4-hydroxy-2-nonenal-induced proteasome dysfunction is correlated with cardiac damage in streptozotocin-injected rats with isoproterenol infusion

Mandar Deshpande, Vishal R. Mali, Guodong Pan, Jiang Xu, Xiao Ping Yang, Rajarajan Amirthalingam Thandavarayan, Suresh Selvaraj Palaniyandi

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Increase in 4-hydroxy-2-nonenal (4HNE) due to oxidative stress has been observed in a variety of cardiac diseases such as diabetic cardiomyopathy. 4HNE exerts a damaging effect in the myocardium by interfering with subcellular organelles like mitochondria by forming adducts. Therefore, we hypothesized that increased 4HNE adduct formation in the heart results in proteasome inactivation in isoproterenol (ISO)-infused type 1 diabetes mellitus (DM) rats. Eight-week-old male Sprague Dawley rats were injected with streptozotocin (STZ, 65 mg kg−1). The rats were infused with ISO (5 mg kg−1) for 2 weeks by mini pumps, after 8 weeks of STZ injection. We studied normal control (n = 8) and DM + ISO (n = 10) groups. Cardiac performance was assessed by echocardiography and Millar catheter at the end of the protocol at 20 weeks. Initially, we found an increase in 4HNE adducts in the hearts of the DM + ISO group. There was also a decrease in myocardial proteasomal peptidase (chymotrypsin and trypsin-like) activity. Increases in cardiomyocyte area (446 ± 32·7 vs 221 ± 10·83) (µm2), per cent area of cardiac fibrosis (7·4 ± 0·7 vs 2·7 ± 0·5) and cardiac dysfunction were also found in DM + ISO (P < 0·05) relative to controls. We also found increased 4HNE adduct formation on proteasomal subunits. Furthermore, reduced aldehyde dehydrogenase 2 activity was observed in the myocardium of the DM + ISO group. Treatment with 4HNE (100 μM) for 4 h on cultured H9c2 cardiomyocytes attenuated proteasome activity. Therefore, we conclude that the 4HNE-induced decrease in proteasome activity may be involved in the cardiac pathology in STZ-injected rats infused with ISO.

Original languageEnglish (US)
Pages (from-to)334-342
Number of pages9
JournalCell Biochemistry and Function
Volume34
Issue number5
DOIs
StatePublished - Jul 1 2016

Keywords

  • 4-hydroxy-2-nonenal
  • cardiac dysfunction and remodelling
  • diabetic heart
  • H9c2 cardiomyocytes
  • proteasome

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Cell Biology

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