Down-regulation of mitofusin-2 expression in cardiac hypertrophy in vitro and in vivo.
Mitofusin-2 (Mfn2) suppresses smooth muscle cell proliferation through inhibition of the Ras-extracellular signal-regulated kinases (ERK1/2) pathway. Since the ERK1/2 pathway is implicated in mediating hypertrophic signaling, we studied the changes in Mfn2 in cardiac hypertrophy using in vitro and in vivo models. Phenylephrine was used to induce hypertrophy in neonatal rat ventricular myocytes (NRVMs). In vivo hypertrophy models included spontaneously hypertensive rats (SHR), pressure-overload hypertrophy by transverse aortic constriction (TAC), hypertrophy of non-infarcted myocardium following myocardial infarction (MI), and cardiomyopathy due to cardiac-restricted overexpression of beta(2)-adrenergic receptors (beta(2)-TG). We determined hypertrophic parameters and analysed expression of atrial natriuretic peptide (ANP) and Mfn2 by real-time PCR. Phosphorylated-ERK1/2 (phospho-ERK) was measured by Western blot. Mfn2 was downregulated in phenylephrine treated NRCMs (by approximately 40%), hypertrophied hearts from SHR (by approximately 80%), mice with TAC (at 1 and 3 weeks, by approximately 50%), and beta(2)-TG mice (by approximately 20%). However, Mfn2 was not downregulated in hypertrophied hearts with 15 weeks of TAC, nor in hypertrophied non-infarcted myocardium following MI. phospho-ERK1/2 was increased in hypertrophied myocardium at 1 week post-TAC, but not in non-infarcted myocardium after MI, indicating that downregulated Mfn2 may be accompanied by an increase of phospho-ERK1/2. This study shows, for the first time, downregulated Mfn2 expression in hypertrophied hearts, which depends on the etiology and time course of hypertrophy. Further study is required to examine the causal relationship between Mfn2 and cardiac hypertrophy.
Fang
Lu
L
Baker Heart Research Institute and Alfred Heart Centre, Alfred Hospital, Melbourne, Australia; Western Hospital, Department of Medicine, University of Melbourne, Melbourne, Australia.
Moore
Xiao-Lei
XL
Baker Heart Research Institute and Alfred Heart Centre, Alfred Hospital, Melbourne, Australia.
Gao
Xiao-Ming
XM
Baker Heart Research Institute and Alfred Heart Centre, Alfred Hospital, Melbourne, Australia.
Dart
Anthony M
AM
Baker Heart Research Institute and Alfred Heart Centre, Alfred Hospital, Melbourne, Australia.
Lim
Yean Leng
YL
Western Hospital, Department of Medicine, University of Melbourne, Melbourne, Australia.
Du
Xiao-Jun
XJ
Baker Heart Research Institute and Alfred Heart Centre, Alfred Hospital, Melbourne, Australia. Electronic address: xiaojun.du@baker.edu.au.
D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D020558:GTP Phosphohydrolases / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000096:biosynthesis*; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse; C489710:Mfn2 protein, rat