TY - JOUR
T1 - Mechanism of Eccentric Cardiomyocyte Hypertrophy Secondary to Severe Mitral Regurgitation
AU - Li, Shujuan
AU - Nguyen, Ngoc Uyen Nhi
AU - Xiao, Feng
AU - Menendez-Montes, Ivan
AU - Nakada, Yuji
AU - Tan, Wilson Lek Wen
AU - Anene-Nzelu, Chukwuemeka George
AU - Foo, Roger S.
AU - Thet, Suwannee
AU - Cardoso, Alisson Campos
AU - Wang, Ping
AU - Elhelaly, Waleed M.
AU - Lam, Nicholas T.
AU - Pereira, Ana Helena Mac Edo
AU - Hill, Joseph A.
AU - Sadek, Hesham A.
N1 - Funding Information:
Dr Sadek is supported by grants from the National Institutes of Health (1R01HL115275 and 5R01H2131778), American Heart Association (16EIA27740034), National Aeronautics and Space Administration (NNX-15AE06G), Cancer Prevention and Research Institute of Texas (RP160520), Hamon Center for Regenerative Science and Medicine, and Fondation Leducq (Redox Regulation of Cardiomyocyte Renewal). Dr Hill is supported by grants from NIH (R01 HL120732, R01 HL128215, R01 HL126012). Dr Nguyen is supported by AHA Postdoctoral Fellowship 19POST34450039. Dr Menendez-Montes is supported by the Alfonso Martin Escudero Foundation fellowship (Spain). Dr Lam is supported by a Haberecht Wildhare-Idea Research Grant. The UTSW mouse MRI facility is supported by an NIH shared instrumentation grant 1S10OD023552-01.
Publisher Copyright:
© 2020 Lippincott Williams and Wilkins. All rights reserved.
PY - 2020/6/2
Y1 - 2020/6/2
N2 - Background: Primary valvular heart disease is a prevalent cause of morbidity and mortality in both industrialized and developing countries. Although the primary consequence of valvular heart disease is myocardial dysfunction, treatment of valvular heart diseases centers around valve repair or replacement rather than prevention or reversal of myocardial dysfunction. This is particularly evident in primary mitral regurgitation (MR), which invariably results in eccentric hypertrophy and left ventricular (LV) failure in the absence of timely valve repair or replacement. The mechanism of LV dysfunction in primary severe MR is entirely unknown. Methods: Here, we developed the first mouse model of severe MR. Valvular damage was achieved by severing the mitral valve leaflets and chords with iridectomy scissors, and MR was confirmed by echocardiography. Serial echocardiography was performed to follow up LV morphology and systolic function. Analysis of cardiac tissues was subsequently performed to evaluate valve deformation, cardiomyocyte morphology, LV fibrosis, and cell death. Finally, dysregulated pathways were assessed by RNA-sequencing analysis and immunofluorescence. Results: In the ensuing 15 weeks after the induction of MR, gradual LV dilatation and dysfunction occurred, resulting in severe systolic dysfunction. Further analysis revealed that severe MR resulted in a marked increase in cardiac mass and increased cardiomyocyte length but not width, with electron microscopic evidence of sarcomere disarray and the development of sarcomere disruption. From a mechanistic standpoint, severe MR resulted in activation of multiple components of both the mammalian target of rapamycin and calcineurin pathways. Inhibition of mammalian target of rapamycin signaling preserved sarcomeric structure and prevented LV remodeling and systolic dysfunction. Immunohistochemical analysis uncovered a differential pattern of expression of the cell polarity regulator Crb2 (crumbs homolog 2) along the longitudinal axis of cardiomyocytes and close to the intercalated disks in the MR hearts. Electron microscopy images demonstrated a significant increase in polysome localization in close proximity to the intercalated disks and some areas along the longitudinal axis in the MR hearts. Conclusions: These results indicate that LV dysfunction in response to severe MR is a form of maladaptive eccentric cardiomyocyte hypertrophy and outline the link between cell polarity regulation and spatial localization protein synthesis as a pathway for directional cardiomyocyte growth.
AB - Background: Primary valvular heart disease is a prevalent cause of morbidity and mortality in both industrialized and developing countries. Although the primary consequence of valvular heart disease is myocardial dysfunction, treatment of valvular heart diseases centers around valve repair or replacement rather than prevention or reversal of myocardial dysfunction. This is particularly evident in primary mitral regurgitation (MR), which invariably results in eccentric hypertrophy and left ventricular (LV) failure in the absence of timely valve repair or replacement. The mechanism of LV dysfunction in primary severe MR is entirely unknown. Methods: Here, we developed the first mouse model of severe MR. Valvular damage was achieved by severing the mitral valve leaflets and chords with iridectomy scissors, and MR was confirmed by echocardiography. Serial echocardiography was performed to follow up LV morphology and systolic function. Analysis of cardiac tissues was subsequently performed to evaluate valve deformation, cardiomyocyte morphology, LV fibrosis, and cell death. Finally, dysregulated pathways were assessed by RNA-sequencing analysis and immunofluorescence. Results: In the ensuing 15 weeks after the induction of MR, gradual LV dilatation and dysfunction occurred, resulting in severe systolic dysfunction. Further analysis revealed that severe MR resulted in a marked increase in cardiac mass and increased cardiomyocyte length but not width, with electron microscopic evidence of sarcomere disarray and the development of sarcomere disruption. From a mechanistic standpoint, severe MR resulted in activation of multiple components of both the mammalian target of rapamycin and calcineurin pathways. Inhibition of mammalian target of rapamycin signaling preserved sarcomeric structure and prevented LV remodeling and systolic dysfunction. Immunohistochemical analysis uncovered a differential pattern of expression of the cell polarity regulator Crb2 (crumbs homolog 2) along the longitudinal axis of cardiomyocytes and close to the intercalated disks in the MR hearts. Electron microscopy images demonstrated a significant increase in polysome localization in close proximity to the intercalated disks and some areas along the longitudinal axis in the MR hearts. Conclusions: These results indicate that LV dysfunction in response to severe MR is a form of maladaptive eccentric cardiomyocyte hypertrophy and outline the link between cell polarity regulation and spatial localization protein synthesis as a pathway for directional cardiomyocyte growth.
KW - Crb2 protein, mouse
KW - hypertrophy
KW - mammalian target of rapamycin
KW - mitral valve insufficiency
KW - polyribosome
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U2 - 10.1161/CIRCULATIONAHA.119.043939
DO - 10.1161/CIRCULATIONAHA.119.043939
M3 - Article
C2 - 32272846
AN - SCOPUS:85085677273
SN - 0009-7322
VL - 141
SP - 1787
EP - 1799
JO - Circulation
JF - Circulation
IS - 22
ER -