Ipertensione arteriosa, scoperta una proteina che ne abbassa i valori

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Si chiama galectina-1 ed è una proteina del corpo in grado di abbassare la pressione arteriosa. In particolare, questa proteina agisce in modo da influenzare la funzione di un’altra proteina di tipo-L del canale del calcio che normalmente agisce per contrarre i vasi sanguigni. Riducendo l’attività di questi canali, la galectina-1 porta così all’abbassamento della pressione del sangue.

Autori della scoperta sono alcuni ricercatori della National University of Singapore, secondo i quali i pazienti con ipertensione di stadio 1 hanno la raccomandazione di cambiare lo stile di vita per ridurre il rischio di soffrire di altre malattie cardiovascolari. Quelli con ipertensione di stadio 2 o superiore devono invece assumere farmaci antipertensivi per controllare la pressione sanguigna. I farmaci che bloccano i canali del calcio sono tradizionalmente usati per abbassarla, ma il loro uso è associato a un rischio maggiore di insufficienza cardiaca nei pazienti ipertesi, in particolare per quelli con problemi cardiaci. Pertanto, lo sviluppo di farmaci che potrebbero regolare l’attività del canale del calcio di tipo L può aprire, secondo gli studiosi, una nuova frontiera per le terapie anti-ipertensive. La ricerca – di cui di seguito riportiamo l’abstract – è stata pubblicata sulla rivista scientifica Circulation.

ABSTRACT
Regulation of Blood Pressure by Targeting CaV1.2-Galectin-1 Protein Interaction

Zhenyu Hu, Guang Li, Jiong-Wei Wang, Suet Yen Chong, Dejie Yu, Xiaoyuan Wang, Jia Lin Soon, Mui Cheng Liang, Yuk Peng Wong, Na Huang, Henry M. Colecraft, Ping Liao, Tuck Wah Soong

BACKGROUND
L-type CaV1.2 channels play crucial roles in regulation of blood pressure. Galectin-1 (Gal-1), has been reported to bind to the I-II loop of CaV1.2 channels to reduce their current density. However, the mechanistic understanding for the down-regulation of CaV1.2 channels by Gal-1, and whether Gal-1 plays a direct role in blood pressure regulation remain unclear.

METHODS
In vitro experiments involving co-IP, western blot, patch-clamp recordings, immunohistochemistry and pressure myography were used to evaluate the molecular mechanisms by which Gal-1 down-regulates CaV1.2 channel in transfected HEK 293 cells, smooth muscle cells, arteries from Lgasl1-/- mice, rat and human patients. In vivo experiments involving delivery of Tat-e9c peptide and AAV5-Gal-1 into rats were performed to investigate the effect of targeting CaV1.2-Gal-1 interaction on blood pressure monitored by tail cuff or telemetry methods.

RESULTS
Our study reveals that Gal-1 is a key regulator for proteasomal degradation of CaV1.2 channels. Gal-1 competed allosterically with CaVβ subunit for binding to the I-II loop of CaV1.2 channel. This competitive disruption of CaVβ binding led to CaV1.2 degradation by exposing the channels to poly-ubiquitination. Notably, we demonstrated that the inverse relationship of reduced Gal-1 and increased CaV1.2 protein levels in arteries was associated with hypertension in hypertensive rats and patients, and Gal-1 deficiency induces higher blood pressure in mice due to up-regulated CaV1.2 protein level in arteries. To directly regulate blood pressure by targeting the CaV1.2-Gal-1 interaction, we administered Tat-e9c, a peptide that competed for binding of Gal-1, by a mini-osmotic pump and this specific disruption of CaV1.2-Gal-1 coupling increased smooth muscle CaV1.2 currents, induced larger arterial contraction and caused hypertension in rats. In contrasting experiments, over-expression of Gal-1 in smooth muscle by a single bolus of AAV5-Gal-1 significantly reduced blood pressure in spontaneously hypertensive rats.

CONCLUSIONS
We have defined molecularly that Gal-1 promotes CaV1.2 degradation by replacing CaVβ and thereby exposing specific lysines for poly-ubiquitination, and by masking I-II loop ER export signals. This mechanistic understanding provided the basis for targeting CaV1.2-Gal-1 interaction to demonstrate clearly the modulatory role Gal-1 plays in regulating blood pressure, and offering a potential approach for therapeutic management of hypertension.