Inhibitory peptide iGal3BP significantly lowers blood pressure in hypertensive rats by blocking Galectin-3/CaV1.2 interaction

Fine-tuning CaV1.2 calcium channel activity is crucial for regulating smooth muscle contraction and blood pressure (BP). Dysregulation of these channels contributes to hypertension, a leading cause of cardiovascular disease. Current antihypertensive therapies often have side effects or limited efficacy in certain patient populations, highlighting the need for novel targets. Galectin-3 (Gal-3) has been identified as a potential CaV1.2-binding protein, but its precise role in modulating CaV1.2 function and its contribution to hypertension pathogenesis remained unclear, representing a critical knowledge gap this study aimed to address.

Researchers conducted a multi-faceted study using in vitro, ex vivo, and in vivo experiments. They utilized transfected HEK 293 cells, isolated smooth muscle cells, and arteries from smooth muscle-specific Gal-3 knockout mice and their wild-type littermates. Human pulmonary artery samples and spontaneously hypertensive rats (SHR) were also examined. Methods included molecular and biochemical assays, in silico prediction, patch-clamp electrophysiologic recordings, immunohistochemistry, pressure myography, and tail-cuff BP measurements. For in vivo intervention, the blocking peptide iGal3BP was delivered into SHR to investigate its effect on blood pressure, with repeated administration to assess sustained effects.

Galectin-3 (Gal-3) was identified as a novel binding partner and an unexpected positive modulator of the CaV1.2 channel, specifically binding to its intracellular II-III loop. This interaction led to increased total and surface expression, current density, and open probability of CaV1.2 channels. Both CaV1.2 and Gal-3 were found to be upregulated in hypertensive rat aortas and human pulmonary arteries. Conditional deletion of Gal-3 in smooth muscle significantly lowered CaV1.2 protein levels and BP in mice. With specific binding sites identified, the peptide iGal3BP, designed to block the 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.

This cumulative effect produced a sustained reduction in BP, demonstrating greater long-lasting antihypertensive effects compared to acute interventions.