Pivotal role of α2 Na⁺ pumps and their high affinity ouabain binding site in cardiovascular health and disease

Abstract

Reduced smooth muscle (SM)-specific α2 Na pump expression elevates basal blood pressure (BP) and increases BP sensitivity to angiotensin II (Ang II) and dietary NaCl, whilst SM-α2 overexpression lowers basal BP and decreases Ang II/salt sensitivity. Prolonged ouabain infusion induces hypertension in rodents, and ouabain-resistant mutation of the α2 ouabain binding site (α2 mice) confers resistance to several forms of hypertension. Pressure overload-induced heart hypertrophy and failure are attenuated in cardio-specific α2 knockout, cardio-specific α2 overexpression and α2 mice. We propose a unifying hypothesis that reconciles these apparently disparate findings: brain mechanisms, activated by Ang II and high NaCl, regulate sympathetic drive and a novel neurohumoral pathway mediated by both brain and circulating endogenous ouabain (EO). Circulating EO modulates ouabain-sensitive α2 Na pump activity and Ca transporter expression and, via Na /Ca exchange, Ca homeostasis. This regulates sensitivity to sympathetic activity, Ca signalling and arterial and cardiac contraction.

An Appraisal of Methods Recently Recommended for Testing Salt Sensitivity of Blood Pressure

“…The mechanisms of salt sensitivity are the subject of ongoing controversy and discussion . Whereas a considerable degree of controversy stems from differing views on the interpretation of specific studies or theories, it can also be related to differences between the methods used to identify subjects with salt sensitivity.…”

Subcellular localization of Na/K-ATPase isoforms in ventricular myocytes

“…We also discovered several novel features that were particularly enabled by STED and STORM imaging: 1) At the outer sarcolemma NKA has no striking structural organization for either α1 or α2; 2) in the TT system NKA-α2 is almost entirely localized to the transverse elements, whereas α1 is similarly prominent in both transverse and longitudinal TT elements Figure 9A 3) NKA-α2 may exhibit some preferential localization just below the TT opening near the SSL; 4) within TT junctional RyR2 sites are not in preferential proximity to NKA-α2 vs. aα1. The latter point appears to dispel the attractive hypothesis that it is selective cleft localization that drives the much higher concentration of NKA-α2 in TT [18, 28] (Figure 9A). …”

“…[24, 25] Selective localization of α2 at such junctional clefts would explain the 4-6-fold higher TT vs. SSL localization of NKA-α2, and could create a local NKA-NCX-RyR nanodomain that could influence local [Na + ] i and [Ca 2+ ] i and contractility. There is precedent for the selective localization of α2 vs. α1 at plasma membrane junctions with the SR or ER in other cell types,[26-28] but definitive data in ventricular myocytes is lacking.…”

Endogenous Ouabain

“…26, 27, 30, 31 The participation of EO is documented by the demonstration that mutation of the ouabain/EO receptor site on α2 Na + pumps to make the pumps ouabain-resistant (α2 R/R ) blocks ouabain-induced and salt-sensitive forms of hyper-tension in mice. 32–35 Importantly, pressure overload-induced cardiac hypertrophy and failure are greatly attenuated in α2 R/R mice, whereas they are accelerated in these mice when the α1 Na + pumps are mutated to an ouabain-sensitive form. 35, 36 (Note: the α1:α2 expression ratio is ≈4:1 in heart and arteries.…”

“…32–35 Importantly, pressure overload-induced cardiac hypertrophy and failure are greatly attenuated in α2 R/R mice, whereas they are accelerated in these mice when the α1 Na + pumps are mutated to an ouabain-sensitive form. 35, 36 (Note: the α1:α2 expression ratio is ≈4:1 in heart and arteries. 37, 38 ) Thus, in addition to hypertension, target organ damage depends, in part, on high affinity EO binding (see “ EO in kidney disease and heart failure ”, below).…”