Decoding post-myocardial infarction coronary microvascular dysfunction: The SP1-driven STAT3/KCa3.1/eNOS protective mechanism.

OBJECTIVE: Coronary microvascular dysfunction following myocardial infarction (MI) serves as a critical factor affecting cardiac repair and functional recovery. Hyperhomocysteinemia (HHcy) has been closely associated with cardiovascular diseases, particularly in terms of its detrimental effects on microvasculature post-MI. Although transcription factor SP1 plays crucial roles in various physiological and pathological processes, its specific mechanism in the reversal of HHcy-induced microvascular dysfunction after MI remains unclear. The purpose of this study was to explore the possible mechanism of SP1 on HHcy-induced microvascular dysfunction. MATERIAL AND METHODS: This study utilized an HHcy mouse model and an in vitro model of human coronary artery endothelial cells (HCAECs) to systematically investigate the role of SP1 in post-MI microvascular dysfunction. Cardiac microvascular perfusion was assessed using fluorescein isothiocyanate (FITC)-labeled tomato lectin. Western blot analysis was employed to examine the expression levels of signal transducer and activator of transcription 3 (STAT3), conductance calcium-activated potassium channel protein 4 (KCNN4, also known as KCa3.1), and endothelial nitric oxide synthase (eNOS). The eNOS inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME) and STAT3 inhibitor Stattic were used to validate the signaling pathway. RESULTS: SP1 considerably improved microvascular dysfunction and angiogenic capacity in HHcy mice after MI. It enhanced cardiac microvascular function recovery by activating the STAT3/KCa3.1/eNOS signaling pathway. The eNOS inhibitor L-NAME reversed the protective effects of SP1, which indicates the crucial role of eNOS in SP1-mediated cardiovascular protection. Furthermore, SP1 alleviated homocysteine and hypoxia-induced cytotoxicity in HCAECs through this pathway, and the inhibition of the STAT3/KCa3.1/eNOS pathway blocked SP1's protective effects. CONCLUSION: This study revealed for the first time the mechanism by which SP1 reverses HHcy-induced post-MI microvascular dysfunction through the activation of the STAT3/KCa3.1/eNOS pathway. The findings not only deepen our understanding of the pathological mechanisms of post-MI microvascular dysfunction but also provide an important theoretical basis for the development of new cardiovascular disease treatment strategies. SP1, as a potential therapeutic target, may play a crucial role in future cardiovascular disease treatments.