Increased 4-hydroxy-2-nonenal-induced proteasome dysfunction is correlated with cardiac damage in streptozotocin-injected rats with isoproterenol infusion.
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) (µm(2) ), 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. Copyright © 2016 John Wiley & Sons, Ltd.
Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
Mandar
M
Deshpande
Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
Vishal R
VR
Mali
Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
Guodong
G
Pan
Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
Jiang
J
Xu
Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
Xiao-Ping
XP
Yang
Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, USA.
Rajarajan A
RA
Thandavarayan
Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.
Suresh Selvaraj
SS
Palaniyandi
D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000378:metabolism; D000447:Aldehydes / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D005355:Fibrosis; D006334:Heart Function Tests / Q000187:drug effects; D006984:Hypertrophy; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D013311:Streptozocin
D000447:Aldehydes; D013311:Streptozocin; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D046988:Proteasome Endopeptidase Complex; C027576:4-hydroxy-2-nonenal; D007545:Isoproterenol
4-hydroxy-2-nonenal; H9c2 cardiomyocytes; cardiac dysfunction and remodelling; diabetic heart; proteasome