Magadum Ajit, Mallaredy Vandana, Roy Rajika, Joladarashi Darukeshwara, Thej Charan, Cheng Zhongjian, Cimini Maria, Truongcao May, Chatoff Adam, Crispim Claudia V, Rigaud Vagner O C, Gonzalez Carolina, Benedict Cindy, Santos Celio X C, Snyder Nathaniel W, Khan Mohsin, Shah Ajay M, Koch Walter J, Kishore Raj
Aging+Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Theranostics. 2025 Jun 18;15(15):7219-7241. doi: 10.7150/thno.112077. eCollection 2025.
The permanent loss of cardiomyocytes (CMs) following myocardial infarction (MI), coupled with the heart's limited regenerative capacity, often leads to heart failure. Phosphoserine aminotransferase 1 (PSAT1) is a protein highly expressed in the embryonic mouse heart but markedly downregulated after birth. Despite its presence in early cardiac development, PSAT1's role in CM proliferation, cardiac physiology, and repair remains unexplored. This study investigates the therapeutic potential of PSAT1-modified mRNA (modRNA) for promoting cardiac repair and improving outcomes post-MI. Synthetic PSAT1-modRNA was delivered to the hearts of mice post-MI. The study evaluated its effects on CM proliferation and death, scar formation, angiogenesis, and cardiac function. Molecular mechanisms underlying PSAT1's actions were explored, including its regulation of the serine synthesis pathway (SSP), oxidative stress, nucleotide synthesis, and interactions with the YAP1-β-catenin molecular axis. Additionally, SSP inhibition studies were conducted to determine its contribution to CM cell cycle activity and apoptosis. PSAT1 is downregulated during mouse heart development. Cardiac delivery of PSAT1-modRNA induced significant CM proliferation, reduced scar size, and enhanced angiogenesis. Functional analyses revealed improved cardiac performance and survival in PSAT1 injected mice post-MI. Mechanistically, PSAT1 induces the serine synthesis pathway (SSP) in CMs, resulting in increased nucleotide synthesis and reduced oxidative stress, thereby supporting CM proliferation and survival Conversely, SSP inhibition suppressed CM cell cycle activity and triggered apoptosis post-MI. Furthermore, PSAT1 modRNA inhibited CM apoptosis by reducing oxidative stress and DNA damage. At the molecular level, YAP1 transactivated PSAT1, and PSAT1 induced β-catenin nuclear translocation, and is indispensable for YAP1-induced CM proliferation. PSAT1 emerges as a pleiotropic gene critical for favorable cardiac remodeling post-MI through multiple mechanisms, including CM proliferation, SSP activation, inhibition of oxidative stress and cell death, and YAP1-β-catenin pathway modulation. These findings highlight PSAT1's potential as a novel therapeutic target for mRNA-based treatments in ischemic heart diseases, offering a promising avenue for clinical application in cardiac repair.
心肌梗死（MI）后心肌细胞（CMs）的永久性丧失，再加上心脏有限的再生能力，常常导致心力衰竭。磷酸丝氨酸转氨酶1（PSAT1）是一种在胚胎小鼠心脏中高度表达但出生后明显下调的蛋白质。尽管其在心脏早期发育中存在，但其在CM增殖、心脏生理和修复中的作用仍未被探索。本研究调查了PSAT1修饰的mRNA（modRNA）促进心脏修复和改善MI后结局的治疗潜力。合成的PSAT1-modRNA在MI后被递送至小鼠心脏。该研究评估了其对CM增殖和死亡、瘢痕形成、血管生成及心脏功能的影响。探索了PSAT1作用的分子机制，包括其对丝氨酸合成途径（SSP）、氧化应激、核苷酸合成的调节以及与YAP1-β-连环蛋白分子轴的相互作用。此外，进行了SSP抑制研究以确定其对CM细胞周期活性和凋亡的作用。PSAT1在小鼠心脏发育过程中下调。心脏递送PSAT1-modRNA可诱导显著的CM增殖、减小瘢痕大小并增强血管生成。功能分析显示，注射PSAT1的MI后小鼠心脏功能改善且生存率提高。从机制上讲，PSAT1在CMs中诱导丝氨酸合成途径（SSP），导致核苷酸合成增加和氧化应激降低，从而支持CM增殖和存活。相反，SSP抑制会抑制CM细胞周期活性并在MI后引发凋亡。此外，PSAT1 modRNA通过降低氧化应激和DNA损伤来抑制CM凋亡。在分子水平上，YAP1反式激活PSAT1，PSAT1诱导β-连环蛋白核转位，并且对于YAP1诱导的CM增殖是不可或缺的。PSAT1通过多种机制成为对MI后有利的心脏重塑至关重要的多效性基因，这些机制包括CM增殖、SSP激活、氧化应激和细胞死亡的抑制以及YAP1-β-连环蛋白途径的调节。这些发现突出了PSAT1作为缺血性心脏病基于mRNA治疗的新型治疗靶点的潜力，为心脏修复的临床应用提供了一条有前景的途径。
