Overexpression of the Na ⁺ /K ⁺ ATPase α2 But Not α1 Isoform Attenuates Pathological Cardiac Hypertrophy and Remodeling

Abstract

Rationale The Na+/K+ ATPase (NKA) directly regulates intracellular Na+ levels, which in turn indirectly regulates Ca2+ levels by proximally controlling flux through the Na+/Ca2+ exchanger (NCX1). Elevated Na+ levels have been reported during heart failure, which permits some degree of reverse mode Ca2+ entry through NCX1, as well as less efficient Ca2+ clearance. Objective To determine if maintaining lower intracellular Na+ levels by NKA overexpression in the heart would enhance forward-mode Ca2+ clearance and prevent reverse-mode Ca2+ entry through NCX1 to protect the heart. Methods and Results Cardiac-specific transgenic mice overexpressing either the NKA-α1 or α2 were generated and subjected to pressure overload hypertrophic stimulation. We found that while increased expression of NKA-α1 had no protective effect, overexpression of NKA-α2 significantly decreased cardiac hypertrophy after pressure overload in mice at 2, 10 and 16 weeks of stimulation. Remarkably, total NKA protein expression and activity were not altered in either of these two transgenic models, as increased expression of one isoform led to a concomitant decrease in the other endogenous isoform. NKA-α2 overexpression, but not NKA-α1, led to significantly faster removal of bulk Ca2+ from the cytosol in a manner requiring NCX1 activity. Mechanistically, overexpressed NKA-α2 showed greater affinity for Na+ compared with NKA-α1, leading to more efficient clearance of this ion. Moreover, overexpression of NKA-α2, but not NKA-α1, was coupled to a decrease in phospholemman expression and phosphorylation, which would favor greater NKA activity, NCX1 activity and Ca2+ removal. Conclusions Our results suggest that the protective effect produced by increased expression of NKA-α2 on the heart after pressure overload is due to more efficient Ca2+ clearance because this isoform of NKA preferentially enhances NCX1 activity compared with NKA-α1.

Expression of rat Na-K-ATPase α2 enables ion pumping but not ouabain-induced signaling in α1-deficient porcine renal epithelial cells

“…Furthermore, replacement of endogenous ouabain-resistant ␣1 with a ouabain-sensitive ␣1 mutant increases both cardiac hypertrophy and fibrosis in pressure-overload models (49). In addition, transgenic overexpression of Na-K-ATPase ␣2 but nor ␣1 attenuated pressureoverload-induced cardiac hypertrophy in a recent study by Correll et al (9). Retrospectively, these in vivo findings are consistent with our new data, indicating that ␣1 is most likely responsible for cardiotonic steroid-induced fibrosis of the heart whereas ␣2, predominantly involved in ion transport, may protect the heart from pressure-overload-induced hypertrophy.…”

“…Retrospectively, these in vivo findings are consistent with our new data, indicating that ␣1 is most likely responsible for cardiotonic steroid-induced fibrosis of the heart whereas ␣2, predominantly involved in ion transport, may protect the heart from pressure-overload-induced hypertrophy. Indeed, overexpression studies strongly suggested that ␣2-mediated protection was promoted through its ability to promote Ca 2ϩ clearance by NCX1 more efficiently than its ␣1 counterpart, rather than through a modulation of the hypertrophic signaling (9). Second, it is important to note that the ␣1 isoform is expressed ubiquitously whereas the ␣2 isoform is primarily found in myocytes.…”

TRPC4α and TRPC4β Similarly Affect Neonatal Cardiomyocyte Survival during Chronic GPCR Stimulation

“…8–12 week old mice (C57/BL/6J) were subjected to TAC or sham surgical procedure to induce chronic left ventricular pressure overload as described previously [13]. The animals were anesthetized with 1.5% isoflurane, intubated, and ventilated with a volume-cycled rodent respirator.…”

Changes in cardiac Na+/K+-ATPase expression and activity in female rats fed a high-fat diet

“…Recently, Correll et al show by overexpressing α1 and α2 tg mice, that only overexpression of α2 subunits of the Na + /K + -ATPase reduced cardiac hypertrophy and remodeling [50]. Furthermore, distribution of α1 and α2 isoforms varies in heart in a region-specific manner [51], even in the same single cell [52].…”