Upregulation of Periostin Through CREB Participates in Myocardial Infarction-induced Myocardial Fibrosis

Abstract

Myocardial fibrosis after myocardial infarction (MI) leads to heart failure, which has become an important global public health issue. One of the most important features of myocardial fibrosis is the abnormal deposition of extracellular matrix (ECM) proteins. Periostin is one of the ECM proteins. Cyclic AMP response element-binding protein 1 (CREB) is well known for its involvement in multiple signaling in myocardial fibrosis. It has been confirmed that CREB could regulate ECM proteins deposition. However, little is known about the relationship between CREB and periostin post-MI. This study aims to verify the hypothesis that CREB promotes the expression of periostin in MI-induced myocardial fibrosis. To test this hypothesis, primary rat cardiac fibroblasts were cultured and rat model of MI was established. The level of myocardial fibrosis post-MI was identified by histological staining. The expressions of CREB and periostin were detected through western blot and reverse transcription quantity polymerase chain reaction. The upregulation and downregulation of CREB and periostin were established by plasmid, small interfere RNA (siRNA), and lentivirus, respectively. High levels of CREB and periostin were found post-MI in our study. Meanwhile, the expression of periostin was decreased after CREB downregulation both in vivo and in vitro. Finally, with the treatment of pAV-CREB and si-periostin, the expressions of collagen Ⅰ and Ⅲ were attenuated. The expression of periostin was elevated post-MI and participated in MI-induced myocardial fibrosis, which was regulated through CREB. This study provides a novel idea and potential intervention target for MI-induced myocardial fibrosis.

Defining cardiac fibrosis complexity and regulation towards therapeutic development

“…At a molecular level, the ECM proteins hyaluronan and fibronectin (ED‐A domain splice variant) are required for myofibroblast differentiation, the latter likely through its interaction with fibroblast‐CD44 100–103 . A wide suite of matricellular proteins including TSP1, 104–107 TSP2, 108,109 TSP4, 110,111 SPARC, 112,113 OPN, 114–116 POSTN, 117,118 also influence disease progression, mechanisms which are incompletely characterized but involve direct interactions with cell receptors. The main mediators of cell‐ECM interactions are integrins, which bind to collagens, fibronectin, and various matricellular proteins, activating intracellular signalling cascades (PI3K/Akt, Raf and MAPKs) via cytoplasmic domains and influencing cell cycle, migration, apoptosis, and differentiation 45 .…”

Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

“…Secreted frizzled protein three protects the heart via ischemic preconditioning in a pig model ( Vatner et al, 2021 ). Upregulation of periostin regulates post-infarct fibrosis via cyclic AMP response element-binding protein 1 ( Xue et al, 2020 ; Xue et al, 2022 ). Anti-proprotein convertase subtilisin/kexin type 9 intervention reduces infarct size and cardiac dysfunction ( Guo et al, 2021 ).…”

Emerging therapies for autosomal dominant polycystic kidney disease with a focus on cAMP signaling

“…In a microarray analysis of cultured human ADPKD cyst epithelial cells, periostin mRNA was markedly overexpressed compared with normal human kidney cells (Wallace et al, 2008). Periostin overexpression, which is important for the development of myocardial infarction induced myocardial fibrosis, can be prevented by siRNA or shRNA CREB downregulation both in vitro and in vivo (Xue et al, 2022). It seems likely that the overexpression of periostin in cystic kidneys is also driven by CREB likely downstream from PKA signaling (Figure 4).…”