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

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.

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.

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.

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.