Circulation · 2026
Galectin-3 Regulates Smooth Muscle Contraction and Blood Pressure by Modulating CaV1.2 Channel Function.
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Loh Kelvin Wei Zhern, Zhou Yanruo, Liu Cong, Zhai Jing, Jaladanki Chaitanya K, Jia Yi Neo Cheryl, Yu Dejie, Liang Mui Cheng, Shen Mengxia, Fan Hao, Liao Ping, Hu Zhenyu, Soong Tuck Wah
Аннотация
BACKGROUND: Fine-tuning of CaV1.2 calcium channel activity by binding proteins represents a novel mechanism for regulating smooth muscle contraction and blood pressure (BP). This study aimed to elucidate the role of Gal-3 (galectin-3), a newly identified CaV1.2-binding protein, in the pathogenesis of hypertension.
METHODS: In vitro, ex vivo, and in vivo experiments involving molecular and biochemical assays, in silico prediction, patch-clamp electrophysiologic recordings, immunohistochemistry, pressure myography, and tail-cuff BP measurements were used to evaluate the molecular mechanisms by which Gal-3 binds to and elevates membrane insertion of CaV1.2 channels. The experiments were performed in transfected HEK 293 cells, isolated smooth muscle cells, and arteries from smooth muscle-specific Gal-3 knockout mice and their wild-type littermates; spontaneously hypertensive rats; or human patients. In vivo experiments involving delivery of the blocking iGal3BP (inhibitory galectin-3-binding peptide) into spontaneously hypertensive rats were performed to investigate its effect on BP.
RESULTS: We identified Gal-3 as a novel binding partner and unexpected positive modulator of the CaV1.2 channel through binding to the intracellular II-III loop. Gal-3 increased total and surface expression, current density, and open probability of CaV1.2 channels. Both CaV1.2 and Gal-3 were upregulated in hypertensive rat aortas and human pulmonary arteries. Conditional deletion of Gal-3 in smooth muscle markedly lowered CaV1.2 protein and BP in mice. With specific binding sites identified within both Gal-3 and the CaV1.2 II-III loop, the peptide iGal3BP, designed to block CaV1.2-Gal-3 interaction, significantly reduced BP in spontaneously hypertensive rats by decreasing CaV1.2 protein expression. Repeated iGal3BP administration resulted in cumulative peptide accumulation in mesenteric arteries and produced a sustained reduction in BP, which demonstrated greater long-lasting antihypertensive efficacy compared with amlodipine and losartan. Administration of iGal3BP in combination with a negative modulatory Gal-1 mimetic peptide that mimics Gal-1-CaV1.2 interaction returned systolic BP to normotensive levels within 4 hours and lowered BP in hypertensive rats in a sustained manner for 35 days.
CONCLUSIONS: These results provide strong evidence that Gal-based CaV1.2 channel modulators are novel therapeutic pathways for normalizing BP.
METHODS: In vitro, ex vivo, and in vivo experiments involving molecular and biochemical assays, in silico prediction, patch-clamp electrophysiologic recordings, immunohistochemistry, pressure myography, and tail-cuff BP measurements were used to evaluate the molecular mechanisms by which Gal-3 binds to and elevates membrane insertion of CaV1.2 channels. The experiments were performed in transfected HEK 293 cells, isolated smooth muscle cells, and arteries from smooth muscle-specific Gal-3 knockout mice and their wild-type littermates; spontaneously hypertensive rats; or human patients. In vivo experiments involving delivery of the blocking iGal3BP (inhibitory galectin-3-binding peptide) into spontaneously hypertensive rats were performed to investigate its effect on BP.
RESULTS: We identified Gal-3 as a novel binding partner and unexpected positive modulator of the CaV1.2 channel through binding to the intracellular II-III loop. Gal-3 increased total and surface expression, current density, and open probability of CaV1.2 channels. Both CaV1.2 and Gal-3 were upregulated in hypertensive rat aortas and human pulmonary arteries. Conditional deletion of Gal-3 in smooth muscle markedly lowered CaV1.2 protein and BP in mice. With specific binding sites identified within both Gal-3 and the CaV1.2 II-III loop, the peptide iGal3BP, designed to block CaV1.2-Gal-3 interaction, significantly reduced BP in spontaneously hypertensive rats by decreasing CaV1.2 protein expression. Repeated iGal3BP administration resulted in cumulative peptide accumulation in mesenteric arteries and produced a sustained reduction in BP, which demonstrated greater long-lasting antihypertensive efficacy compared with amlodipine and losartan. Administration of iGal3BP in combination with a negative modulatory Gal-1 mimetic peptide that mimics Gal-1-CaV1.2 interaction returned systolic BP to normotensive levels within 4 hours and lowered BP in hypertensive rats in a sustained manner for 35 days.
CONCLUSIONS: These results provide strong evidence that Gal-based CaV1.2 channel modulators are novel therapeutic pathways for normalizing BP.