Abstract Objective To study the changes and significance of apoptosis signal-regulating kinase 1 (ASK1) in left ventricular remodeling in FVB/N mice. Methods A total of 54 FVB/N mice were randomly divided into 4 groups:0 d group with 8 mice, 7 d group with 10 mice, 14 d group with 16 mice, and 21 d group with 20 mice. A model of cardiac remodeling was established by intraperitoneal injection of isoproterenol (ISO) at a daily dose of 30 mg/kg, and the 7 d, 14 d, and 21 d groups were injected for 7, 14, and 21 consecutive days respectively. The 0 d group was given intraperitoneal injection of an equal volume of normal saline. Echocardiography was used to measure left ventricular posterior wall thickness at end diastole (dLVPW) and the ratio of heart weight to tibia length (HW/TL) was measured. Hematoxylin-eosin staining was used to measure left ventricular myocardial fiber diameter. Picric-Sirius red staining was used to measure myocardial collagen deposition area in the left ventricle. Quantitative real-time PCR was used to measure the mRNA expression of ASK1, type I collagen (collagen I), and B-type natriuretic peptide (BNP). The mortality rate was observed for each group. Results There were gradual increases in HW/TL, myocardial fiber diameter, and dLVPW after 0, 7, and 14 days of ISO injection (P < 0.05). There were no significant changes in HW/TL ratio and dLVPW from days 14 to 21 of ISO injection (P > 0.05), while there was a significant reduction in myocardial fiber diameter (P < 0.05), which was similar to the value on day 7 (P > 0.05). There were significant increases in myocardial collagen deposition area and the mRNA expression of collagen I, ASK1, and BNP after 0, 7, 14, and 21 days of ISO injection, which reached the peaks on day 21 (P < 0.01). The mRNA expression of ASK1 was positively correlated with myocardial collagen deposition area and the mRNA expression of collagen I and BNP and had a weak correlation with HW/TL, myocardial fiber diameter, and dLVPW. There was a significant increase in the mortality rate of the mice over the time of ISO injection. Conclusions The expression of ASK1 in the myocardium is closely associated with left ventricular remodeling. The increase of ASK1 expression may lead to the aggravation of left ventricular remodeling, and the mechanism of which needs further study.
YUAN Yong-Hua,XIA Xiao-Hui,HE Xue-Hua et al. Role of apoptosis signal-regulating kinase 1 in left ventricular remodeling in mice[J]. CJCP, 2019, 21(10): 1049-1054.
YUAN Yong-Hua,XIA Xiao-Hui,HE Xue-Hua et al. Role of apoptosis signal-regulating kinase 1 in left ventricular remodeling in mice[J]. CJCP, 2019, 21(10): 1049-1054.
Ichijo H, Nishida E, Irie K, et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways[J]. Science, 1997, 275(5296):90-94.
[2]
Huang Q, Zhou HJ, Zhang H, et al. Thioredoxin-2 inhibits mitochondrial reactive oxygen species generation and apoptosis stress kinase-1 activity to maintain cardiac function[J]. Circulation, 2015, 131(12):1082-1097.
[3]
Boucherat O, Provencher S, Bonnet S. Therapeutic value of ASK1 inhibition in pulmonary arterial hypertension[J]. Am J Respir Crit Care Med, 2018, 197(3):284-286.
Budas GR, Boehm M, Kojonazarov B, et al. ASK1 inhibition halts disease progression in preclinical models of pulmonary arterial hypertension[J]. Am J Respir Crit Care Med, 2018, 197(3):373-385.
[6]
Hartupee J, Mann DL. Neurohormonal activation in heart failure with reduced ejection fraction[J]. Nat Rev Cardiol, 2017, 14(1):30-38.
Yamaguchi O, Higuchi Y, Hirotani S, et al. Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling[J]. Proc Natl Acad Sci U S A, 2003, 100(26):15883-15888.
[9]
Li L, Chen Y, Doan J, et al. Transforming growth factor β-activated kinase 1 signaling pathway critically regulates myocardial survival and remodeling[J]. Circulation, 2014, 130(24):2162-2172.
[10]
Guo X, Yin H, Li L, et al. Cardioprotective role of tumor necrosis factor receptor-associated factor 2 by suppressing apoptosis and necroptosis[J]. Circulation, 2017, 136(8):729-742.
[11]
Teerlink JR, Pfeffer JM, Pfeffer MA. Progressive ventricular remodeling in response to diffuse isoproterenol-induced myocardial necrosis in rats[J]. Circ Res, 1994, 75(1):105-113.
[12]
Mohamed BA, Schnelle M, Khadjeh S, et al. Molecular and structural transition mechanisms in long-term volume overload[J]. Eur J Heart Fail, 2016, 18(4):362-371.
[13]
Patel VB, McLean BA, Chen X, et al. Regulators of G-protein signaling 10 and heart failure:the importance of negative regulators of heart disease[J]. Hypertension, 2016, 67(1):38-40.
[14]
Sharp TE, Schena GJ, Hobby AR, et al. Cortical bone stem cell therapy preserves cardiac structure and function after myocardial infarction[J]. Circ Res, 2017, 121(11):1263-1278.
[15]
Hou L, Guo J, Xu F, et al. Cardiomyocyte dimethylarginine dimethylaminohydrolase1 attenuates left-ventricular remodeling after acute myocardial infarction:involvement in oxidative stress and apoptosis[J]. Basic Res Cardiol, 2018, 113(4):28.
[16]
Shan X, Wang H, Margulies KB. Apoptosis signal-regulating kinase 1 attenuates atrial natriuretic peptide secretion[J]. Biochemistry, 2008, 47(38):10041-10048.
[17]
Toldo S, Breckenridge DG, Mezzaroma E, et al. Inhibition of apoptosis signal-regulating kinase 1 reduces myocardial ischemia-reperfusion injury in the mouse[J]. J Am Heart Assoc, 2012, 1(5):e002360.
[18]
Gerczuk PZ, Breckenridge DG, Liles JT, et al. An apoptosis signal-regulating kinase 1 inhibitor reduces cardiomyocyte apoptosis and infarct size in a rat ischemia-reperfusion model[J]. J Cardiovasc Pharmacol, 2012, 60(3):276-282.
[19]
Lanier M, Pickens J, Bigi SV, et al. Structure-based design of ASK1 inhibitors as potential agents for heart failure[J]. ACS Med Chem Lett, 2017, 8(3):316-320.
[20]
Wu Y, Qian Z, Fu S, et al. Icarisidell improves left ventricular remodeling in spontaneously hypertensive rats by inhibiting the ASK1-JNK/p38 signaling pathway[J]. Eur J Pharmacol, 2018, 819:68-79.
[21]
Nakamura T, Kataoka K, Fukuda M, et al. Critical role of apoptosis signal-regulating kinase 1 in aldosterone/salt-induced cardiac inflammation and fibrosis[J]. Hypertension, 2009, 54(3):544-551.
