Crim1 inhibits angiotensin II-induced hypertrophy and preserves Kv4.2 expression in cardiomyocytes

Document Type : Original Article

Authors

Department of Cardiology, Guizhou Provincial People’s Hospital, Guiyang 550002 China

Abstract

Objective(s): Angiotensin II (Ang II) plays a key role in the regulation of myocardial hypertrophy via downstream cysteine-rich transmembrane bone morphogenetic protein regulator 1 (Crim1). However, it is still unclear whether Crim1 is involved in ionic channel remodeling. The study aimed to explore the effects of Crim1 on transient outward potassium current (Ito) and Kv4.2 (the main subunit of Ito channel) expression in hypertrophic ventricular cardiomyocytes. 
Materials and Methods: The ventricular cardiomyocytes were isolated from the neonatal rats. Hypertrophy was induced by Ang II. Crim1 expression was modulated by using adenovirus transfection. The expression of myosin heavy chain beta (β-MHC), Crim1, and Kv4.2 was determined by RT-qPCR and western blot. The cellular surface area was assessed using Image J software. Ito was recorded by the whole-cell patch clamp technique. 
Results: Ang II-induced hypertrophy in cardiomyocytes was identified by their larger cellular surface area and higher mRNA expression of β-MHC. Ang II significantly decreased the expression of Crim1 and Kv4.2 and reduced Ito current density. However, Crim1 overexpression abolished the Ang II-induced hypertrophy and preserved the expression of Kv4.2 and Ito current density. 
Conclusion: Crim1 overexpression inhibits Ang II-induced hypertrophy and preserves Ito current density via up-regulating Kv4.2 in ventricular cardiomyocytes from neonatal rats. Crim1 could have a role in the development of ventricular arrhythmia in hypertrophic hearts.

Keywords

References

1. Ippei S, Tohru M. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol 2016; 97:245-262.
2. Oldfield CJ, Duhamel TA, Dhalla NS. Mechanisms for the transition from physiological to pathological cardiac hypertrophy. Can J Physiol Pharmacol 2020; 98:74-84.
3. Huang D, Hua W, Fang Q, Yan J, Su Y, Liu B, et al. Biventricular pacemaker and defibrillator implantation in patients with chronic heart failure in China. ESC Heart Fail 2021; 8:546-554.
4. Wang Y, Hill JA. Electrophysiological remodeling in heart failure. J Mol Cell Cardiol 2010; 48:619-632.
5. Kepenek ES, Ozcinar E, Tuncay E, Akcali KC, Akar AR, Turan B. Differential expression of genes participating in cardiomyocyte electrophysiological remodeling via membrane ionic mechanisms and Ca(2+)-handling in human heart failure. Mol Cell Biochem 2020; 463:33-44.
6. Fiset C, Clark RB, Shimoni Y, Giles WR. Shal-type channels contribute to the Ca2+-independent transient outward K+ current in rat ventricle. J Physiol 1997; 500 (Pt 1):51-64.
7. Guo W, Li H, Aimond F, Johns DC, Rhodes KJ, Trimmer JS, et al. Role of heteromultimers in the generation of myocardial transient outward K+ currents. Circ Res 2002; 90:586-593.
8. Wang Z, Feng J, Shi H, Pond A, Nerbonne JM, Nattel S. Potential molecular basis of different physiological properties of the transient outward K+ current in rabbit and human atrial myocytes. Circ Res 1999; 84:551-561.
9.    Guo W, Jung WE, Marionneau C, Aimond F, Xu H, Yamada KA, et al. Targeted deletion of Kv4.2 eliminates I(to,f) and results in electrical and molecular remodeling, with no evidence of ventricular hypertrophy or myocardial dysfunction. Circ Res 2005; 97:1342-1350.
10.   Sadoshima J, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 1993; 75:977-984.
11.    Sadoshima J, Izumo S. Molecular characterization of angiotensin II--induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res 1993; 73:413-423.
12. Tyan L, Turner D, Komp KR, Medvedev RY, Lim E, Glukhov AV. Caveolin-3 is required for regulation of transient outward potassium current by angiotensin II in mouse atrial myocytes. Am J Physiol Heart Circ Physiol 2021; 320:H787-H797.
13.    Sun B, Huo R, Sheng Y, Li Y, Xie X, Chen C, et al. Bone morphogenetic protein-4 mediates cardiac hypertrophy, apoptosis, and fibrosis in experimentally pathological cardiac hypertrophy. Hypertension 2013; 61:352-360.
14.    Glienke J, Sturz A, Menrad A, Thierauch KH. CRIM1 is involved in endothelial cell capillary formation in vitro and is expressed in blood vessels in vivo. Mech Dev 2002; 119:165-175.
15.    Nakashima Y, Takahashi S. Induction of cysteine-rich motor neuron 1 mRNA expression in vascular endothelial cells. Biochem Biophys Res Commun 2014; 451:235-238.
16.    Iyer S, Chou FY, Wang R, Chiu HS, Raju VK, et al. Crim1 has cell-autonomous and paracrine roles during embryonic heart development. Sci Rep 2016; 6:19832.
17.    Iyer S, Pennisi DJ, Piper M. Crim1-, a regulator of developmental organogenesis. Histol Histopathol 2016; 31:1049-1057.
18.    Ahsan M, Li X, Lundberg AE, Kierczak M, Siegel PB, Carlborg O, et al. Identification of candidate genes and mutations in QTL regions for chicken growth using bioinformatic analysis of NGS and SNP-chip data. Front Genet 2013; 4:226-233.
19.    Pennisi DJ, Wilkinson L, Kolle G, Sohaskey ML, Gillinder K, Piper MJ, et al. Crim1KST264/KST264 mice display a disruption of the Crim1 gene resulting in perinatal lethality with defects in multiple organ systems. Dev Dyn 2007; 236:502-511.
20.    Chiu HS, York JP, Wilkinson L, Zhang P, Little MH, Pennisi DJ. Production of a mouse line with a conditional Crim1 mutant allele. Genesis 2012; 50:711-716.
21.   Garcia Abreu J, Coffinier C, Larraín J, Oelgeschläger M, De Robertis EM. Chordin-like CR domains and the regulation of evolutionarily conserved extracellular signaling systems. Gene 2002; 287:39-47.
22.    Larraín J, Bachiller D, Lu B, Agius E, Piccolo S, De Robertis EM. BMP-binding modules in chordin: a model for signalling regulation in the extracellular space. Development 2000; 127:821-830.
23.    Wilkinson L, Kolle G, Wen D, Piper M, Scott J, Little M. CRIM1 regulates the rate of processing and delivery of bone morphogenetic proteins to the cell surface. J Biol Chem 2003; 278:34181-34188.
24.    Yang L, He J, Xia G, Yang J, Tang Q, Yang Y, et al. Crim1 suppresses left ventricular hypertrophy. Biomed Rep 2019; 1:1-5.
25.    Golden HB, Gollapudi D, Gerilechaogetu F, Li J, Cristales RJ, Peng X, et al. Isolation of cardiac myocytes and fibroblasts from neonatal rat pups. Methods Mol Biol 2012; 843:205-214.
26.    Yang L, Deng N, He J, Xia G, Yang Y, Zhao Y, et al. Calcineurin Aβ gene knockdown inhibits transient outward potassium current ion channel remodeling in hypertrophic ventricular myocyte. Open Life Sci 2021; 16:1010-1021.
27.    Sriramula S, Francis J. Tumor necrosis factor - alpha is essential for angiotensin ii-induced ventricular remodeling: role for oxidative stress. PLoS One 2015; 10:e0138372.
28.    Palaniyappan A, Uwiera RR, Idikio H, Menon V, Jugdutt C, Jugdutt BI. Attenuation of increased secretory leukocyte protease inhibitor, matricellular proteins and angiotensin II and left ventricular remodeling by candesartan and omapatrilat during healing after reperfused myocardial infarction. Mol Cell Biochem 2013; 376:175-188.
29.    Kohno T, Anzai T, Naito K, Sugano Y, Maekawa Y, Takahashi T, et al. Angiotensin-receptor blockade reduces border zone myocardial monocyte chemoattractant protein-1 expression and macrophage infiltration in post-infarction ventricular remodeling. Circ J 2008; 72:1685-1692.
30.    Sármán B, Skoumal R, Leskinen H, Rysä J, Ilves M, Soini Y, et al. Nuclear factor-kappaB signaling contributes to severe, but not moderate, angiotensin II-induced left ventricular remodeling. J Hypertens 2007; 25:1927-1939.
31.    Zhang SJ, Yun CJ, Liu J, Yao SY, Li Y, Wang M, et al. MicroRNA-29a attenuates angiotensin-II induced-left ventricular remodeling by inhibiting collagen, TGF-β and SMAD2/3 expression. J Geriatr Cardiol 2020; 17:96-104.
32.    He J, Xu Y, Yang L, Xia G, Deng N, Yang Y, et al. Regulation of inward rectifier potassium current ionic channel remodeling by AT(1) -Calcineurin-NFAT signaling pathway in stretch-induced hypertrophic atrial myocytes. Cell Biol Int 2018; 42:1149-1159.
33. Iravanian S, Sovari AA, Lardin HA, Liu H, Xiao HD, Dolmatova E, et al. Inhibition of renin-angiotensin system (RAS) reduces ventricular tachycardia risk by altering connexin43. J Mol Med (Berl) 2011; 89:677-687.
34.    Kasi VS, Xiao HD, Shang LL, Iravanian S, Langberg J, et al. Cardiac-restricted angiotensin-converting enzyme overexpression causes conduction defects and connexin dysregulation. Am J Physiol Heart Circ Physiol 2007; 293:H182-192.
35.    Gou X, Wang W, Zou S, Qi Y, Xu Y. Protein kinase C epsilon mediates the inhibition of angiotensin II on the slowly activating delayed-rectifier potassium current through channel phosphorylation. J Mol Cell Cardiol 2018; 116:165-174.
36.    Binas S, Knyrim M, Hupfeld J, Kloeckner U, Rabe S, Mildenberger S, et al. miR-221 and -222 target CACNA1C and KCNJ5 leading to altered cardiac ion channel expression and current density. Cell Mol Life Sci 2020; 77:903-918.
37.    Taigen T, De Windt LJ, Lim HW, Molkentin JD. Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A 2000; 97:1196-1201.
38.    Rossow CF, Minami E, Chase EG, Murry CE, Santana LF. NFATc3-induced reductions in voltage-gated K+ currents after myocardial infarction. Circ Res 2004; 94:1340-1350.
39.    Gong N, Bodi I, Zobel C, Schwartz A, Molkentin JD, Backx PH. Calcineurin increases cardiac transient outward K+ currents via transcriptional up-regulation of Kv4.2 channel subunits. J Biol Chem 2006; 281:38498-38506.
40.    Guo Y, Zhang C, Ye T, Chen X, Liu X, Chen X, et al. Pinocembrin ameliorates arrhythmias in rats with chronic ischaemic heart failure. Ann Med 2021; 53:830-840.
Iranian Journal of Basic Medical Sciences
Volume 25, Issue 10
October 2022
Pages 1201-1206

Files

Share

How to cite

Statistics