Sp1 Targeted PARP1 Inhibition Protects Cardiomyocytes From Myocardial Ischemia–Reperfusion Injury via Downregulation of Autophagy

Abstract

Myocardial ischemia–reperfusion injury (MIRI), characterized by post-ischemic cardiomyocytes death and reperfusion myocardial damage, is a lethal yet unresolved complication in the treatment of acute myocardial infarction (AMI). Previous studies have demonstrated that poly(ADP-ribose) polymerase-1 (PARP1) participates in the progression of various cardiovascular diseases, and various reports have proved that PARP1 can be a therapeutic target in these diseases, but whether it plays a role in MIRI is still unknown. Therefore, in this study, we aimed to explore the role and mechanism of PARP1 in the development of MIRI. Firstly, we demonstrated that PARP1 was activated during MIRI-induced myocardial autophagy in vitro. Moreover, PARP1 inhibition protected cardiomyocytes from MIRI through the inhibition of autophagy. Next, we discovered that specificity protein1 (Sp1), as a transcription factor of PARP1, regulates its target gene PARP1 through binding to its target gene promoter during transcription. Furthermore, silencing Sp1 protected cardiomyocytes from MIRI via the inhibition of PARP1. Finally, the functions and mechanisms of PARP1 in the development of MIRI were also verified in vivo with SD rats model. Based on these findings, we concluded that PARP1 inhibition protects cardiomyocytes from MIRI through the inhibition of autophagy, which is targeted by Sp1 suppression. Therefore, the utilization of PARP1 exhibits great therapeutic potential for MIRI treatment in future.

Signaling Pathways Involved in Myocardial Ischemia–Reperfusion Injury and Cardioprotection: A Systematic Review of Transcriptomic Studies in Sus scrofa

“…In the IC, several TFs were differentially expressed during the first and second windows post-infarction (≤3 days) including JUN, STAT3, ATF2, ESR1, SPI1, RELA, RUNX1, STAT1, MYC, ETS1, GATA2, KLF4, NELFE, and STAT6 ( Figure 3 A). Many of these early response TFs are cardioprotective and mediate DNA damage responses, metabolic regulation, immunity, and inflammation [ 39 , 40 , 41 ]. In contrast, the AR, CTNNB1, and EGR1 were identified as upregulated TFs throughout the acute and chronic stages (≥3 days), which correlates with their role in modulating transcriptional programs associated with resolution and repair in response to tissue injury [ 42 , 43 , 44 ].…”

Expression Pattern and Molecular Mechanism of Oxidative Stress-Related Genes in Myocardial Ischemia–Reperfusion Injury

“…Previous studies have shown that miR-29b-3p can aggravate myocardial I/R injury by regulating HMCN1 or cIAP1 [ 36 ]. There are also related studies reporting the critical role of these TFs (Nfkb1, Rela, Sp1, and Usf2) in the process of MIRI [ 37 , 38 ]. On the basis of the drug-related datasets, 21 therapeutic drugs (such as ritonavir, staurosporine, simvastatin, lutein, aspirin, warfarin, and clofibrate) that regulate OSRGs were predicted.…”

Long Noncoding RNA SNHG4 Attenuates the Injury of Myocardial Infarction via Regulating miR-148b-3p/DUSP1 Axis

“…Evidence has determined that lncRNAs can be regulated by many core transcription factors, such as SP1, NF-κB, p53, and SOX2 [52]. These transcription factors also play an important role in regulating myocardial injury [53][54][55][56]. In addition, the protective role of DUSP1 in myocardial injury has been determined to be closely associated the downstream pathways of JNK [51,57] and MAPK [58].…”