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Published on: December 9, 2020
Galectin-1 attenuates cardiomyocyte hypertrophy through splice-variant specific modulation of CaV1.2 calcium channel
Jia Fan1, Wenyong Fan1, Jianzhen Lei1
1Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Insights
Galectin-1 (Gal-1) inhibits cardiac calcium channel CaV1.2 expression, reducing intracellular calcium and preventing cardiomyocyte hypertrophy. This suggests Gal-1 as a potential therapeutic target for heart conditions.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Calcium Channel Regulation
Background:
- Cardiac hypertrophy results from pressure overload, involving CaV1.2 calcium channel dysfunction and altered intracellular calcium ([Ca2+]i).
- Galectin-1 (Gal-1), a carbohydrate-binding protein, interacts with CaV1.2 channels, influencing vascular function and blood pressure.
- The role of Gal-1 in cardiac CaV1.2 channels (CaV1.2CM) and cardiomyocyte hypertrophy is not well understood.
Purpose of the Study:
- To investigate the function of Gal-1 in regulating CaV1.2CM activity and its impact on cardiomyocyte hypertrophy.
- To elucidate the molecular mechanisms by which Gal-1 affects CaV1.2CM and downstream signaling pathways.
- To explore the potential of Gal-1 and its splice variants as therapeutic targets for cardiac hypertrophy.
Main Methods:
- Whole-cell patch clamp electrophysiology in neonatal rat ventricular myocytes (NRVMs) and HEK293 cells.
- Measurement of intracellular calcium ([Ca2+]i) levels.
- Western blotting to assess protein phosphorylation and translocation (δCaMKII, HDAC4).
- Analysis of Gal-1 and CaV1.2 alternative exon 9* expression in hypertrophic cardiomyocytes and hearts.
Main Results:
- Gal-1 significantly reduces L-type calcium currents (ICa,L) by decreasing CaV1.2CM membrane expression in NRVMs.
- Gal-1 inhibits CaV1.2CM currents in a splice-variant specific manner (exon 9*) in HEK293 cells.
- Overexpression of Gal-1 attenuates isoproterenol (ISO)-induced increases in [Ca2+]i and cardiomyocyte hypertrophy.
- Gal-1 inhibits the phosphorylation of δCaMKII and HDAC4, and suppresses HDAC4 translocation in response to ISO.
- Expression of Gal-1 and CaV1.2E9* channels is elevated in hypertrophic rat cardiomyocytes and hearts.
Conclusions:
- Gal-1 inhibits CaV1.2CM currents via a splice-variant specific mechanism, reducing [Ca2+]i and attenuating cardiac hypertrophy.
- The inhibitory effect of Gal-1 on hypertrophy involves suppressing the δCaMKII and HDAC4 signaling pathway.
- Dysregulation of Gal-1 and CaV1.2 alternative exon 9* expression contributes to pathological cardiac hypertrophy, presenting a potential therapeutic target.
Abstract:
Pressure overload-induced cardiac hypertrophy occurs in response to chronic blood pressure increase, and dysfunction of CaV1.2 calcium channel involves in cardiac hypertrophic processes by perturbing intracellular calcium concentration ([Ca2+]i) and calcium-dependent signaling. As a carbohydrate-binding protein, galectin-1 (Gal-1) is found to bind with CaV1.2 channel, which regulates vascular CaV1.2 channel functions and blood pressure. However, the potential roles of Gal-1 in cardiac CaV1.2 channel (CaV1.2CM) and cardiomyocyte hypertrophy remain elusive. By whole-cell patch clamp, we find Gal-1 decreases the ICa,L with or without isoproterenol (ISO) application by reducing the channel membrane expression in neonatal rat ventricular myocytes (NRVMs). Moreover, Gal-1 could inhibit the current densities of CaV1.2CM by an alternative exon 9*-dependent manner in heterologously expressed HEK293 cells. Of significance, overexpression of Gal-1 diminishes ISO or KCl-induced [Ca2+]i elevation and attenuates ISO-induced hypertrophy in NRVMs. Mechanistically, Gal-1 decreases the ISO or Bay K8644-induced phosphorylation of intracellular calcium-dependent signaling proteins δCaMKII and HDAC4, and inhibits ISO-triggered translocation of HDAC4 in NRVMs. Pathologically, we observe that the expressions of Gal-1 and CaV1.2E9* channels are synchronously increased in rat hypertrophic cardiomyocytes and hearts. Taken together, our study indicates that Gal-1 reduces the channel membrane expression to inhibit the currents of CaV1.2CM in a splice-variant specific manner, which diminishes [Ca2+]i elevation, and attenuates cardiomyocyte hypertrophy by inhibiting the phosphorylation of δCaMKII and HDAC4. Furthermore, our work suggests that dysregulated Gal-1 and CaV1.2 alternative exon 9* might be attributed to the pathological processes of cardiac hypertrophy, and provides a potential anti-hypertrophic target in the heart.
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