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Updated: May 16, 2026
In vitro Assessment of Myocardial Protection following Hypothermia-Preconditioning in a Human Cardiac Myocytes Model
Published on: October 27, 2020
Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart
Jian Xie1, Seung-Kuy Cha, Sung-Wan An
1Department of Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
Insights
Klotho protein protects the heart from stress-induced damage by downregulating TRPC6 channels. Klotho deficiency worsens cardiac hypertrophy, while its overexpression improves heart function and survival.
Area of Science:
- Cardiology
- Molecular Biology
- Gerontology
Background:
- Aging increases heart failure risk.
- The cardioprotective role of Klotho remains unclear.
- Klotho is a kidney-produced membrane protein with anti-aging properties.
Purpose of the Study:
- Investigate Klotho's role in cardiac protection.
- Determine the mechanism of Klotho's cardioprotective effects.
- Explore therapeutic potential for cardiomyopathies.
Main Methods:
- Utilized Klotho-deficient and TRPC6-overexpressing mouse models.
- Assessed cardiac hypertrophy and remodeling in response to stress.
- Investigated TRPC6 channel regulation by Klotho in cardiomyocytes.
Main Results:
- Klotho deficiency exacerbates stress-induced cardiac hypertrophy and remodeling.
- Klotho-mediated cardioprotection involves TRPC6 channel downregulation.
- TRPC6 channel overexpression in the heart causes spontaneous cardiac pathology.
- Soluble Klotho inhibits TRPC6 currents by blocking channel exocytosis.
Conclusions:
- Klotho is a key regulator of cardiac TRPC6 channels.
- TRPC6 channels are critical mediators of Klotho's cardioprotective effects.
- Targeting the Klotho-TRPC6 axis offers novel therapeutic strategies for heart disease.
Abstract:
Klotho is a membrane protein predominantly produced in the kidney that exerts some antiageing effects. Ageing is associated with an increased risk of heart failure; whether Klotho is cardioprotective is unknown. Here we show that Klotho-deficient mice have no baseline cardiac abnormalities but develop exaggerated pathological cardiac hypertrophy and remodelling in response to stress. Cardioprotection by Klotho in normal mice is mediated by downregulation of TRPC6 channels in the heart. We demonstrate that deletion of Trpc6 prevents stress-induced exaggerated cardiac remodelling in Klotho-deficient mice. Furthermore, mice with heart-specific overexpression of TRPC6 develop spontaneous cardiac hypertrophy and remodelling. Klotho overexpression ameliorates cardiac pathologies in these mice and improves their long-term survival. Soluble Klotho present in the systemic circulation inhibits TRPC6 currents in cardiomyocytes by blocking phosphoinositide-3-kinase-dependent exocytosis of TRPC6 channels. These results provide a new perspective on the pathogenesis of cardiomyopathies and open new avenues for treatment of the disease.
