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Apoptosis signal-regulating kinase 1 deficiency eliminates cardiovascular injuries induced by high-salt diet
Keiichiro Kataoka1, Yoshiko Tokutomi, Eiichiro Yamamoto
1Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Objectives:
High-salt diet is closely associated with the increase in cardiovascular events. However, the mechanism of high-salt-induced cardiovascular injury is unknown. The present study was undertaken to test our hypothesis that apoptosis signal-regulating kinase (ASK) 1 may be involved in salt-induced cardiovascular injury.
Methods:
Wild-type and ASK1-/- mice were fed a low-salt or a high-salt diet for 10 weeks and the effects of high-salt diet on food intake, urinary volume and electrolyte excretion, and cardiovascular injury were compared between both groups of mice.
Results:
High-salt diet in wild-type and ASK1-/- mice similarly increased food intake, water intake, urine volume, and urinary sodium excretion, and comparably decreased plasma renin activity and aldosterone. Thus, ASK1 appears to play a minor role in the increase in natriuresis and the decrease in plasma renin, and aldosterone caused by high-salt diet. High-salt diet enhanced the phosphorylation of cardiovascular ASK1 in wild-type mice. High-salt diet in wild-type mice enhanced cardiac transforming growth factor-β1, interstitial fibrosis, coronary perivascular fibrosis, and inflammatory cell infiltration, and these changes were associated with the increase in cardiac superoxide and Nox2. ASK1 deficiency abolished the above-mentioned high-salt-induced cardiac injury. High-salt diet also caused the impairment of vascular endothelium-dependent relaxation by acetylcholine and increased vascular superoxide, and Nox2 in wild-type mice, whereas it did not cause vascular injury in ASK1-/- mice.
Conclusion:
ASK1 is implicated in cardiac inflammation and fibrosis, and vascular endothelial dysfunction caused by high-salt diet, through the enhancement of oxidative stress.
Insights
High-salt diets cause cardiovascular injury by activating apoptosis signal-regulating kinase 1 (ASK1), leading to cardiac inflammation, fibrosis, and vascular dysfunction through oxidative stress.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Renal Physiology
Background:
- High-salt intake is a significant risk factor for cardiovascular events.
- The precise mechanisms underlying high-salt-induced cardiovascular damage remain incompletely understood.
- Apoptosis signal-regulating kinase 1 (ASK1) is a potential mediator in cellular stress responses.
Purpose of the Study:
- To investigate the role of ASK1 in high-salt-induced cardiovascular injury.
- To determine if ASK1 deficiency mitigates the adverse effects of a high-salt diet on the cardiovascular system.
Main Methods:
- Wild-type and ASK1 knockout (ASK1-/-) mice were subjected to either a low-salt or high-salt diet for 10 weeks.
- Parameters assessed included food and water intake, urinary output, electrolyte excretion, and cardiovascular tissue analysis.
- Cardiovascular function, oxidative stress markers (superoxide, Nox2), inflammation, fibrosis, and vascular reactivity were evaluated.
Main Results:
- High-salt diet increased food intake, water intake, urine volume, and sodium excretion similarly in both wild-type and ASK1-/- mice.
- ASK1 deficiency did not significantly alter natriuresis or the decrease in plasma renin and aldosterone induced by high salt.
- High-salt diet enhanced ASK1 phosphorylation, cardiac inflammation, fibrosis, oxidative stress, and vascular endothelial dysfunction in wild-type mice, effects abolished by ASK1 deficiency.
Conclusions:
- Apoptosis signal-regulating kinase 1 (ASK1) plays a critical role in mediating high-salt-induced cardiac inflammation, fibrosis, and vascular endothelial dysfunction.
- The detrimental effects of high-salt diet on the cardiovascular system are, in part, driven by ASK1-dependent oxidative stress.
- Targeting ASK1 may offer a therapeutic strategy to prevent or treat salt-sensitive cardiovascular diseases.
