Journal Article

BS20 Sodium-bicarbonate co-transport produces a milieu that is conducive for pro-hypertrophic signalling in cardiomyocytes

Gill, Eleanor, Loonat, Aminah, Baark, Friedrich, Richards, Mark, Hulikova, Alzbeta, Curtis, Kate, Monterisi, Stefania, White, Bobby, Wilson, Abigail, Clark, James, Swietach, Pawel

2025

Overview

RationaleMaladaptive cardiac hypertrophy predisposes individuals to heart failure. However, current treatments are inaccessible to drugs, and are therefore unsuitable for slowing the progression of hypertrophy. The cell-surface SLC proteins NHE (Slc9a1), NBCe1 (Slc4a4) and NBCn1 (Slc4a7), which are more therapeutically accessible, are critical in neutralising the pH of the highly metabolic cardiomyocytes, and are associated with both physiological and pathophysiological cellular growth. In particular, NBCn1, the electroneutral Na+-HCO3- transporter, is associated with pro-hypertrophic growth in cardiomyocytes and may be of therapeutic interest.MethodsCardiac hypertrophy was evoked in vivo in wildtype or Slc4a7 knockout mice by chemical stressors or abdominal aortic banding (AAB), and changes in cardiac function were assessed by echocardiography. Neonatal rat ventricular myocytes (NRVMs) treated with phenylephrine (PE). Assessment ofResultsNRVMs treated with 10μM PE at pH 7.4 and 24mM HCO3- exhibited increased GATA4 phosphorylation, Anp expression and SRB staining, indicative of increased protein production and consequent hypertrophy. However, these changes were attenuated both at pH 6.4 and in the presence of the pan-NBC inhibitor S0859. However, only Slc4a7 and not Slc4a4 expression was increased in hypertrophic NRVMs, and NBCn1 activity is higher in PE-treated NRVMs at pH 7.4, suggesting that HCO3- transport may be important. In fact, increased PE-induced GATA4 phosphorylation, Anp/Bnp expression and SRB staining was dependent on HCO3-. Moreover, HCO3- was critical for activation of the pro-hypertrophic mTOR signalling cascade and ribosome biogenesis.AAB increased diastolic LV diameter and wall thickness, associated with reduced ejection fraction and fractional shortening; however, these differences were ablated following treatment with S0859. Infusion of isoproterenol via minipumps also resulted in increased myocyte area, and increased Slc4a7 expression and NBCn1 activity in pro-hypertrophic hearts. Additionally, infusion of isoproterenol into Slc4a7 knockout mice exhibited reduced cardiac hypertrophy and left ventricular posterior wall thickness, associated with delayed progression of systolic dysfunction and better cardiac output and stroke volume, demonstrating the importance of the role of NBCn1 in vivo.ConclusionsNBCn1 is the predominant isoform involved in HCO3- dependent alkalinisation and cardiomyocyte hypertrophy, both in vitro and in vivo. It is therefore an attractive therapeutic target for the prevention of cardiac hypertrophy and heart failure.

• Publisher: BMJ Publishing Group LTD
• Subject: Cardiomyocytes / Heart failure / Phosphorylation