Overexpressing Mitogen-activated Protein Kinase Kinase 7 (MKK7) Alleviates Endoplasmic Reticulum Stress-induced Cardiac Dysfunction during Pressure Overload induced Heart Failure

Tayyiba Azam; Min Zi; Susanne S. Hille; Hongyuan Zhang; Elizabeth J. Cartwright; Oliver J. Müller; Xin Wang

doi:10.53941/ijddp.2023.100013

Abstract

Since its emergence as a cardiovascular epidemic in 1997, heart failure (HF) continues to be a significant challenge globally both economically and in clinical practice. As a consequence of the lack of effective treatments available, significant efforts have been devoted with the aim of identifying novel therapeutic strategies to treat HF. Loss of Mitogen-activated Protein Kinase Kinase 7 (MKK7) in the myocardium has previously been shown to underpin ventricular hypertrophy and HF progression. We demonstrated that adeno-associated virus 9 (AAV9) cardiac-specific overexpression of MKK7 therapeutically impeded cardiac dysfunction, interstitial fibrosis and cardiomyocytes apoptosis following 5-weeks pressure overload-induced HF. It was found that this was achieved, at least partly, by ameliorating Endoplasmic Reticulum (ER) stress. Mechanistically, in vivo and in vitro analysis revealed that although overexpression of MKK7 had no effect on PERK-ATF4 or ATF6 signalling pathways, the IRE1-XBP1 signalling pathway was preserved and a hindered increase in CHOP expression was observed. In conclusion, overexpression of MKK7 holds therapeutic potential in mitigating the pathological cardiac changes associated with HF progression.

References

1.
Nakamura, M.; Sadoshima, J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat. Rev. Cardiol. 2018, 15, 387–407.
2.
Riehle, C.; Bauersachs, J. Small animal models of heart failure. Cardiovasc. Res. 2019, 115, 1838–1849.
3.
Liu, M.; Liu, H.; Parthiban, P.; et al. Inhibition of the unfolded protein response reduces arrhythmia risk after myocardial infarction. J. Clin. Invest. 2021, 131, e147836 .
4.
Blackstone, C.; Prinz,Keeping in shape, W.A.. Elife 2016, 5, e20468 .
5.
Perkins, H.T.; Allan, V.J.; Waigh, T.A. Network organisation and the dynamics of tubules in the endoplasmic reticulum. Sci. Rep. 2021, 11, 16230.
6.
Hofmann, C.; Katus, H.A.; Doroudgar, S. Protein Misfolding in Cardiac Disease. Circulation 2019, 139, 2085–2088.
7.
Jin, J.K.; Blackwood, E.A.; Azizi, K.; et al. ATF6 Decreases Myocardial Ischemia/Reperfusion Damage and Links ER Stress and Oxidative Stress Signalling Pathways in the Heart. Circ. Res. 2017, 120, 862–875.
8.
Bhatta, M.; Chatpar, K.; Hu, Z.; et al. Reduction of Endoplasmic Reticulum Stress Improves Angiogenic Progenitor Cell function in a Mouse Model of Type 1 Diabetes. Cell Death Dis. 2018, 9, 467.
9.
Yao, Y.; Lu, Q.; Hu, Z.; et al. A non-canonical pathway regulates ER stress signalling and blocks ER stress-induced apoptosis and heart failure. Nat. Commun. 2017, 8, 133.
10.
Binder, P.; Wang, S.; Radu, M.; et al. Pak2 as a Novel Therapeutic Target for Cardioprotective Endoplasmic Reticulum Stress Response. Circ. Res. 2019, 124, 696–711.
11.
Al-Yacoub, N.; Colak, D.; Mahmoud, S.A.; et al. Mutation in FBXO32 causes dilated cardiomyopathy through up-regulation of ER-stress mediated apoptosis. Commun. Biol. 2021, 4, 884.
12.
Hetz, C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat. Rev. Mol. Cell Biol. 2012, 13, 89–102.
13.
Liu, W.; Zi, M.; Chi, H.; et al. Deprivation of MKK7 in cardiomyocytes provokes heart failure in mice when exposed to pressure overload. J. Mol. Cell Cardiol. 2011, 50, 702–711.
14.
Chowdhury, S.K.; Liu, W.; Zi, M.; et al. Stress-Activated Kinase Mitogen-Activated Kinase Kinase-7 Governs Epigenetics of Cardiac Repolarization for Arrhythmia Prevention. Circulation. 2017, 135, 683–699.
15.
Liang, Q.; Bueno, O.F.; Wilkins, B.J.; et al. c-Jun N-terminal kinases (JNK) antagonize cardiac growth through cross-talk with calcineurin-NFAT signalling. EMBO J., 2003, 22, 5079–5089.
16.
Shao, Z.; Bhattacharya, K.; Hsich, E.; et al. c-Jun N-terminal kinases mediate reactivation of Akt and cardiomyocyte survival after hypoxic injury in vitro and in vivo. Circ. Res. 2006, 98, 111–118.
17.
Petrich, B.G.; Eloff, B.C.; Lerner, D.L.; et al. Targeted activation of c-Jun N-terminal kinase in vivo induces restrictive cardiomyopathy and conduction defects. J. Biol. Chem., 2004, 279, 15330–15338.
18.
Wang, J.; Wang, H.; Chen, J.; et al. GADD45B inhibits MKK7-induced cardiac hypertrophy and the polymorphisms of GADD45B is associated with inter-ventricular septum hypertrophy. Biochem. Biophys. Res. Commun. 2008, 372, 623–628.
19.
Pandey, V.K.; Mathur, A.; Kakkar, P. Emerging role of Unfolded Protein Response (UPR) mediated proteotoxic apoptosis in diabetes. Life Sci. 2019, 216, 246–258.
20.
Liu, C.L.; Li, X.; Gan, L.; et al. High-content screening identifies inhibitors of the nuclear translocation of ATF6. Int. J. Mol. Med. 2016, 37, 407–414.
21.
Gao, G.; Xie, A.; Zhang, J.; et al. Unfolded protein response regulates cardiac sodium current in systolic human heart failure. Circ. Arrhythm. Electrophysiol. 2013, 6, 1018–1024.
22.
Amen, O.M.; Sarker, S.D.; Ghildyal, R.; et al. Arya, A. Endoplasmic Reticulum Stress Activates Unfolded Protein Response Signalling and Mediates Inflammation, Obesity, and Cardiac Dysfunction: Therapeutic and Molecular Approach. Front. Pharmacol. 2019, 10, 977.
23.
Dorsch, L.M.; Schuldt, M.; dos Remedios, C.G.; et al. Protein Quality Control Activation and Microtubule Remodelling in Hypertrophic Cardiomyopathy. Cells 2019, 8, 741.
24.
Shirakabe, A.; Ikeda, Y.; Sciarretta, S.; et al. Aging and Autophagy in the Heart. Circ. Res. 2016, 118, 1563–1576.
25.
Wang, X.; Deng, Y.; Zhang, G.; et al. Spliced X-box Binding Protein 1 Stimulates Adaptive Growth Through Activation of mTOR. Circulation 2019, 140, 566–579.
26.
Duan, Q.; Ni, L.; Wang, P.; et al. Deregulation of XBP1 expression contributes to myocardial vascular endothelial growth factor-A expression and angiogenesis during cardiac hypertrophy in vivo. Aging Cell 2016, 15, 625–633.
27.
Steiger, D.; Yokota, T.; Li, J.; et al. The serine/threonine-protein kinase/endoribonuclease IRE1α protects the heart against pressure overload-induced heart failure. J. Biol. Chem. 2018, 293, 9652–9661
28.
Hu, H.; Tian, M.; Ding, C.; et al. The C/EBP Homologous Protein (CHOP) Transcription Factor Functions in Endoplasmic Reticulum Stress-Induced Apoptosis and Microbial Infection. Front. Immunol. 2019, 9, 3083.
29.
Fu, H.Y.; Okada, K.; Liao, Y.; et al. Ablation of C/EBP homologous protein attenuates endoplasmic reticulum-mediated apoptosis and cardiac dysfunction induced by pressure overload. Circulation 2010, 122, 361–369
30.
Finnson, K.W.; Almadani, Y.; Philip, A. Non-canonical (non-SMAD 2/ 3) TGF-β signalling in fibrosis: Mechanisms and targets. Semin. Cell Dev. Biol. 2020, 101, 115–122.
31.
Ma, Z.G.; Yuan, Y.P.; Wu, H.M.; et al. Cardiac fibrosis: new insights into the pathogenesis. Int. J. Biol. Sci. 2018, 14, 1645–1657.
32.
Leivonen, S.K.; Lazaridis, K.; Decock, J.; et al. TGF-β-elicited induction of tissue inhibitor of metalloproteinases (TIMP)-3 expression in fibroblasts involves complex interplay between Smad3, p38α, and ERK1/2. PLoS One 2013, 8, e57474 .
33.
Sadoshima, J.; Montagne, O.; Wang, Q.; et al. The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy. J. Clin. Invest. 2002, 110, 271–279.
34.
Calamaras, T.D.; Baumgartner, R.A.; Aronovitz, M.J.; et al. Mixed lineage kinase-3 prevents cardiac dysfunction and structural remodelling with pressure overload. Am. J. Physiol. Heart Circ. Physiol. 2019, 316, H145–H159.

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