Knockout of the Na,K-ATPase α<sub>2</sub>-isoform in cardiac myocytes delays pressure overload-induced cardiac dysfunction

Rindler, Tara N.; Lasko, Valerie M.; Nieman, Michelle L.; Okada, Motoi; Lorenz, John N.; Lingrel, Jerry B.

doi:10.1152/ajpheart.00594.2012

Cited by 22 publications

(29 citation statements)

References 39 publications

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“…However, two landmark, but underappreciated, articles published in this journal, and a more recent report in Circulation Research, in which transaortic constriction (TAC), a common model, was used to induce pressure overload, have demonstrated that this view is not entirely correct. Notably, experiments on mice with genetically engi-neered cardiac ␣ 2 -Na ϩ pumps can exhibit substantial TACinduced elevation of LV systolic pressure (LVSP) but greatly attenuated cardiac hypertrophy and dysfunction (15,82,112). Those observations, which are summarized here, provide the basis for a new explanation for how pressure overload triggers the cardiac structural and functional changes that characterize hypertrophy ( Figs.…”

mentioning

confidence: 81%

How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na⁺pumps are crucial

Blaustein

2017

American Journal of Physiology-Heart and Circulatory Physiology

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Left ventricular hypertrophy is frequently observed in hypertensive patients and is believed to be due to the pressure overload and cardiomyocyte stretch. Three recent reports on mice with genetically engineered Na pumps, however, have demonstrated that cardiac ouabain-sensitive α-Na pumps play a key role in the pathogenesis of transaortic constriction-induced hypertrophy. Hypertrophy was delayed/attenuated in mice with mutant, ouabain-resistant α-Na pumps and in mice with cardiac-selective knockout or transgenic overexpression of α-Na pumps. The latter, seemingly paradoxical, findings can be explained by comparing the numbers of available (ouabain-free) high-affinity (α) ouabain-binding sites in wild-type, knockout, and transgenic hearts. Conversely, hypertrophy was accelerated in α-ouabain-resistant (R) mice in which the normally ouabain-resistant α-Na pumps were mutated to an ouabain-sensitive (S) form (αα or "SWAP" vs. wild-type or α α mice). Furthermore, transaortic constriction-induced hypertrophy in SWAP mice was prevented/reversed by immunoneutralizing circulating endogenous ouabain (EO). These findings show that EO and its receptor, ouabain-sensitive α, are critical factors in pressure overload-induced cardiac hypertrophy. This complements reports linking elevated plasma EO to hypertension, cardiac hypertrophy, and failure in humans and elucidates the underappreciated role of the EO-Na pump pathway in cardiovascular disease.

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confidence: 81%

How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na⁺pumps are crucial

Blaustein

2017

American Journal of Physiology-Heart and Circulatory Physiology

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“…Peripheral vascular resistance is defined as the ratio of mean blood pressure (mmHg) to blood flow rate (μl min −1 ) (Rindler et al . ).…”

Section: Methodsmentioning

confidence: 97%

“…The tail-cuff measurements were also done in anaesthetized mice. Peripheral vascular resistance is defined as the ratio of mean blood pressure (mmHg) to blood flow rate (μl min −1 ) (Rindler et al 2011).…”

Section: No Measurementsmentioning

confidence: 99%

Inwardly rectifying K⁺ channels are major contributors to flow‐induced vasodilatation in resistance arteries

Ahn

Fancher

Bian

et al. 2016

The Journal of Physiology

110

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Key pointsr Endothelial inwardly rectifying K + (Kir2.1) channels regulate flow-induced vasodilatation via nitric oxide (NO) in mouse mesenteric resistance arteries.r Deficiency of Kir2.1 channels results in elevated blood pressure and increased vascular resistance.r Flow-induced vasodilatation in human resistance arteries is also regulated by inwardly rectifying K + channels.r This study presents the first direct evidence that Kir channels play a critical role in physiological endothelial responses to flow.Abstract Inwardly rectifying K + (Kir) channels are known to be sensitive to flow, but their role in flow-induced endothelial responses is not known. The goal of this study is to establish the role of Kir channels in flow-induced vasodilatation and to provide first insights into the mechanisms responsible for Kir signalling in this process. First, we establish that primary endothelial cells isolated from murine mesenteric arteries express functional Kir2.1 channels sensitive to shear stress. Then, using the Kir2.1 +/− heterozygous mouse model, we establish that downregulation of Kir2.1 results in significant decrease in shear-activated Kir currents and inhibition of endothelium-dependent flow-induced vasodilatation (FIV) assayed in pressurized mesenteric arteries pre-constricted with endothelin-1. Deficiency in Kir2.1 also results in the loss of flow-induced phosphorylation of eNOS and Akt, as well as inhibition of NO generation. All the effects are fully rescued by endothelial cell (EC)-specific overexpression of Kir2.1. A component of FIV that is Kir independent is abrogated by blocking Ca 2+ -sensitive K + channels. Kir2.1 has no effect on endothelium-independent and K + -induced vasodilatation in denuded arteries. Kir2.1 +/− mice also show increased mean blood pressure measured by carotid artery cannulation and increased microvascular resistance measured using a tail-cuff. Importantly, blocking Kir channels also inhibits flow-induced vasodilatation in human subcutaneous adipose microvessels. Endothelial Kir channels contribute to FIV of mouse mesenteric arteries via an NO-dependent mechanism, whereas Ca 2+ -sensitive K + channels mediate FIV via an NO-independent pathway. Kir2 channels also regulate vascular resistance and blood pressure. Finally, Kir channels also contribute to FIV in human subcutaneous microvessels.

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“…increased end‐diastolic and systolic volumes, and decreased ejection fraction (EF) (Rindler et al . ). However, cardio‐specific α2, but not α1, overexpression also attenuates TAC‐induced HH (Correll et al .…”

Section: Introductionmentioning

confidence: 97%

“…These considerations also explain why both cardiac‐α2 knockout (Rindler et al . ) and overexpression (Correll et al . ) delay/attenuate TAC‐induced cardiac dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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

Blaustein

Chen

Hamlyn

et al. 2016

The Journal of Physiology

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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.

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Knockout of the Na,K-ATPase α₂-isoform in cardiac myocytes delays pressure overload-induced cardiac dysfunction

Cited by 22 publications

References 39 publications

How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na⁺pumps are crucial

How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na⁺pumps are crucial

Inwardly rectifying K⁺ channels are major contributors to flow‐induced vasodilatation in resistance arteries

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

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Knockout of the Na,K-ATPase α2-isoform in cardiac myocytes delays pressure overload-induced cardiac dysfunction

Cited by 22 publications

References 39 publications

How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na+pumps are crucial

How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na+pumps are crucial

Inwardly rectifying K+ channels are major contributors to flow‐induced vasodilatation in resistance arteries

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

Contact Info

Product

Resources

About

Knockout of the Na,K-ATPase α₂-isoform in cardiac myocytes delays pressure overload-induced cardiac dysfunction

How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na⁺pumps are crucial

How does pressure overload cause cardiac hypertrophy and dysfunction? High-ouabain affinity cardiac Na⁺pumps are crucial

Inwardly rectifying K⁺ channels are major contributors to flow‐induced vasodilatation in resistance arteries

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