CARDIOVASCULAR JOURNAL OF AFRICA • Volume 33, No 6, November/December 2022 308 AFRICA are presented in Tables 2 to 4 and Fig. 5. GO analysis revealed that numerous target genes were involved in the biological processes, such as regulation of transcription, regulation of transcription from RNA polymerase II promoter and regulation of DNA-dependent transcription. These processes were associated with transcription factors and co-factors underlying the preventative effects of VRP on pressure overload-induced ventricular arrhythmias. KEGG pathway analysis revealed that DEGs were enriched in the top 10 pathways following VRP treatment (Table 5, Fig. 6). Especially among these pathways, the mitogen-activated protein kinase (MAPK) signalling pathway was identified as the most enriched pathway related to myocytes. Construction of the PPI network The up- and downregulated PPI network was constructed. The top four genes, namely Rac1 (degree = 41), Grb2 (degree = 30), Rbm8a (degree = 24) and Mapk1 (degree = 23) were identified as the specific functional genes associated with verapamil on pressure overload-induced ventricular arrhythmias (Fig. 7). Discussion Mechanical overload produces ventricular arrhythmias, which are significantly related to the occurrence of early afterdepolarisations, shortening the duration of the monophasic action potential plateau.21 The development of high-throughput technology has led to the detection of many genes/proteins that are involved in mechano-electric feedback. Over the last few decades, the molecular mechanism of mechanosensitivity in the heart and cardiac myocytes has been of great research interest. As was previously reported, the acute stretch of cardiac myocytes leads to rapid multiple alterations of intracellular signal-transduction pathways.22 However, the molecular mechanisms underlying the preventative effects of VRP related to pressure overload-induced ventricular arrhythmia remain uncharacterised. Therefore, we thoroughly investigated the anti-arrhythmic effects of VRP involved in mechano-electric feedback at the molecular level. In this study, transient stretch caused an acute increase in LVSP and LVEDP and subsequently produced ventricular arrhythmias. This study demonstrates that VRP application (0.5 and 1 mg/kg) significantly reduced wall stress-induced VASs in rats. VRP exerted its steady-state anti-arrhythmic effect Acadl Pdk2 Rpl31 Eefla2 Clic5 Coa5 Ryr2 Hipk2 LOC688018 Ogdh Ldb3 LOC100360791 Tp53inp2 Atp5d Dlc1 Rac1 Best1 Bag3 Vegfa LOC102553290 Rb11b Epas1 Srrm2 Dynll2 Rnpepl1 Pabpc4 Sod3 Hrc Tns1 Nfia Pcbp1 Rnfl10 Atp6v0c Sptbn1 Zfp36l1 Yqhae Dmpk Tcf4 LOC313641 Fth1 Uqcrb Vwf Synpo2 Hspb7 Rsrp1 Got1 Rnr2 Parm1 Pdia3 Eifl Aes Ptms Rn5–8s Htra3 Fem1a Gja1 Sorbs1 Gpx3 Eng Trnk Hspb6 Cmya5 Gpc1 LOC500712 LOC100233206 LOC100362110 Ucp2 LOC102547101 Rn45s Aldh2 Nfe2l1 Lamb2 Pde4dip LOC102556059 LOC103692592 Cox6a2 Pink1 Twf2 Tml1 LOC103693757 LOC310926 Trni Trnm Trnr Rnr1 Trnn LOC103690939 LOC103691943 Trnh Trnq Mgp Penk Hbb LOC102723236 Nppb Rmrp Rps21 Tnnc1 Nppa group 2–1 group 2–3 group 2–2 group 4–1 group 4–2 group 4–3 –1 0 1 Row Z score Fig. 4. Hierarchical cluster analysis of the DEGs among three randomly selected rats in groups 2 and 4. The colour code in the heat map is linear; red indicates increased gene expression and blue represents reduced gene expression. Genes limited to the top 100 are displayed in the heat map. Table 4. Top 10 GO-MF analysis of DEGs between groups 2 and 4 Term Description Count p-value GO:0030528 Transcription regulator activity 151 4.09E-22 GO:0008134 Transcription factor binding 64 7.73E-17 GO:0016563 Transcription activator activity 57 1.85E-14 GO:0019899 Enzyme binding 79 5.53E-14 GO:0003677 DNA binding 152 1.84E-12 GO:0003700 Transcription factor activity 90 2.78E-12 GO:0003712 Transcription co-factor activity 37 4.95E-11 GO:0008092 Cytoskeletal protein binding 61 2.06E-10 GO:0016564 Transcription repressor activity 43 3.87E-10 GO:0043565 Sequence-specific DNA binding 71 4.85E-10 GO: gene ontology; MF: molecular function; DEGs: differentially expressed genes.
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