PRMT7 ablation in cardiomyocytes causes cardiac hypertrophy and fibrosis through β-catenin dysregulation

Abstract

Angiotensin II (AngII) has potent cardiac hypertrophic effects mediated through activation of hypertrophic signaling like Wnt/b-Catenin signaling. In the current study, we examined the role of protein arginine methyltransferase 7 (PRMT7) in cardiac function. PRMT7 was greatly decreased in hypertrophic hearts chronically infused with AngII and cardiomyocytes treated with AngII. PRMT7 depletion in rat cardiomyocytes resulted in hypertrophic responses. Consistently, mice lacking PRMT7 exhibited displayed the cardiac hypertrophy and brosis. PRMT7 overexpression abrogated the cellular hypertrophy elicited by AngII, while PRMT7 depletion exacerbated the hypertrophic response caused by AngII. Similar with AngII treatment, the cardiac transcriptome analysis of PRMT7-de cient hearts revealed the alteration in gene expression pro le related to Wnt signaling pathway. Inhibition of PRMT7 by gene deletion or an inhibitor treatment enhanced the activity of b-Catenin. PRMT7 de ciency decreases symmetric dimethylation of b-Catenin. Mechanistic studies reveal that methylation of arginine residue 93 in b-Catenin decreases the activity of b-Catenin. Taken together, our data suggest that PRMT7 is important for normal cardiac function through suppression of b-Catenin activity.

PRMT7 Inhibitor SGC8158 Enhances Doxorubicin-Induced DNA Damage and Its Cytotoxicity

“…As a distinguishing feature from other PRMTs, PRMT7 generates only MMA on its substrate proteins and contains two SAM-binding motifs required for its methyltransferase activity [ 8 , 9 ]. In addition to histones (H2B at R29/R31/R33 and H4 at R17/R19) [ 9 ], PRMT7 methylates non-histone substrates including Dvl3 [ 32 ], G3BP2 [ 33 ], eIF2α [ 34 ], Hsp70 [ 13 ], and β-catenin [ 7 ]. In addition, since PRMT7 overexpression has been implicated in various cancers, including breast cancer and leukemia [ 10 , 11 ], PRMT7 is emerging as a potential target for cancer treatment.…”

“…Type I PRMTs (PRMT1, 2, 3, 4, 6, and 8) generate both MMA and ADMA, whereas type II PRMTs (PRMT5 and 9) produce both MMA and SDMA [ 4 , 5 ]. PRMT7 produces only MMA on its substrate proteins, including histones (H3, H4, H2B, and H2A) and non-histone proteins (DVL3, G3BP2, eIF2α, Hsp70, and β-catenin), and is classified as a type III enzyme [ 6 , 7 ]. PRMT7 has two S-adenosylmethionine (SAM)-binding motifs that are required for its methyltransferase activity [ 8 , 9 ].…”

Cdon suppresses vascular smooth muscle calcification via repression of the Wnt/Runx2 Axis

“…Echocardiography was carried out using a Vevo LAZR-X machine (the BIORP of Korea Basic Science Institute) with a 40-MHz probe (visual sonic). Analysis of M-mode images derived from the short-axis view of the left ventricle was carried out to measure the ejection fraction and fractional shortening 19 . PWV was obtained from the B-mode and pulse-waved (PW) Doppler mode of the aortic arch view, calculated as PWV = aortic arch distance/transit time (cm/s).…”

Cdon suppresses Vascular Smooth Muscle Calcification via Repression of Wnt/Runx2 axis

“…Echocardiography was carried out using a Vevo LAZR-X machine (the BIORP of Korea Basic Science Institute) with a 40-MHz probe (visual sonic). Analysis of M-mode images derived from the short-axis view of the left ventricle was carried out to measure the ejection fraction (EF) and the fractional shortening (FS) 19 . PWV was obtained from the Bmode and pulse-waved (PW) doppler mode of aortic arch view, calculated as PWV=Aortic arch distance/transit time (cm/s).…”