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

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^R/R 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^R/R 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 Ca²⁺ transporter expression and, via Na⁺/Ca²⁺ exchange, Ca²⁺ homeostasis. This regulates sensitivity to sympathetic activity, Ca²⁺ signalling and arterial and cardiac contraction. (Figure presented.).