Substance P Administered after Myocardial Infarction Upregulates Microphthalmia-Associated Transcription Factor, GATA4, and the Expansion of c-Kit+ Cells.

Yun-Mi Jeong,Weon Kim,Xian Wu Cheng

doi:10.1155/2020/1835950

Abstract

Microphthalmia-associated transcription factor (MITF), a basic helix-loop-helix leucine zipper transcription factor, can govern gene expression by binding to E box elements in the promoter region of its target gene. Although high levels of MITF have been observed in cardiomyocytes and the heart, the role of MITF after myocardial infarction (MI) remains unclear. We investigated the association between substance P (SP)/neurokinin-1 receptor (NK1R) signaling and MITF expression after MI. Male Sprague-Dawley rats (8 weeks) were randomly divided in two groups: ischemia/reperfusion injury (I/R) and SP injection (5 nmol/kg, SP+I/R). At the end of 7 days, the left ventricle (LV; LV7daysI/R, LV7daysSP+I/R) and infarct-related areas (IA; IA7daysI/R, IA7daysSP+I/R) from the hearts were collected. Immunofluorescence staining demonstrated that the LV7daysSP+I/R had a larger population of c-Kit+ GATA4high cells, which markedly upregulated MITF, c-Kit, and GATA4. c-Kit+ cells in the explant-derived cells (EDCs) derived from IA7daysSP+I/R migrated more widely than EDCs IA7daysI/R. Immunofluorescence staining, western blot analysis, and qRT-PCR assay showed that SP-treated c-Kit+ cells exhibited a high expression of c-Kit, GATA4, and MITF. FTY720 (a MITF inhibitor), RP67580 (NK1R inhibitor), or both inhibited the migration and proliferation of c-Kit+ cells increased by SP and blocked the upregulation of c-Kit, GATA4, and MITF. Overall, we suggest that MITF might be a potential regulator in SP-mediated c-Kit+ cell expansion post-MI via c-Kit and GATA4.

Highlights

Heart failure (HF) is expected to grow as an important clinical and public health challenge
These analyses revealed a significant increase in c-Kit, GATA4, and Microphthalmia-associated transcription factor (MITF) expression in LV7daysSP+I/R compared to LV7daysI/R (Figure 4)
GATA expression in LV7daysSP+I/R at the mRNA level markedly increased (Figure 4(c)). These results provide evidence that the molecular pathways of substance P (SP) might induce the expansion of endogenous resident c-Kit+ GATA4highexpressed cells, which are associated with c-Kit, GATA4, and MITF expression

Summary

Introduction

Heart failure (HF) is expected to grow as an important clinical and public health challenge. The mechanisms underlying cardiac growth, cardiac hypertrophy, and LV remodeling are still poorly understood, their intricate interactions might involve endogenous resident c-Kit+ cells and cardiomyocytes lost through direct injury [3,4,5]. Endothelin-1, angiotensin II, natriuretic peptides, and/or α1 and β-adrenergic agonists might play a substantial modulatory role in cardiac remodeling [4]. Cardiac transcription factors (such as GATA4, Nkx2.5, TBX5, and MEF2) and chromatin remodeling enzymes are involved in stress regulation of the adult heart [5, 6]. Gaining a more precise understanding of the molecular mechanisms governing transcriptional regulation during postinfarct LV remodeling would be helpful in the development of novel strategies for HF therapies

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Results

Conclusion