Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart

Xie, Jingyuan; Kuy, Seung; An, Sung Wan; Kuro‐o, Makoto; Birnbaumer, Lutz; Huang, Chou Long

doi:10.1038/ncomms2240

Cited by 288 publications

(315 citation statements)

References 57 publications

(104 reference statements)

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“…32 Moreover, cardioprotection of Klotho was proposed to act through suppression of the TRPC6 signal pathway. 31 Klotho mRNA was found in the sinoatrial node, 32 but membrane Klotho protein has never been shown to be expressed in cardiomyocytes or cardiac fibroblasts. We are primarily examining a different aspect of Klotho biology, which is the systemic effects of soluble Klotho.…”

Section: Discussionmentioning

confidence: 99%

Klotho and Phosphate Are Modulators of Pathologic Uremic Cardiac Remodeling

Hu¹,

Shi²,

Cho³

et al. 2015

Journal of the American Society of Nephrology

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Cardiac dysfunction in CKD is characterized by aberrant cardiac remodeling with hypertrophy and fibrosis. CKD is a state of severe systemic Klotho deficiency, and restoration of Klotho attenuates vascular calcification associated with CKD. We examined the role of Klotho in cardiac remodeling in models of Klotho deficiencygenetic Klotho hypomorphism, high dietary phosphate intake, aging, and CKD. Klotho-deficient mice exhibited cardiac dysfunction and hypertrophy before 12 weeks of age followed by fibrosis. In wild-type mice, the induction of CKD led to severe cardiovascular changes not observed in control mice. Notably, non-CKD mice fed a high-phosphate diet had lower Klotho levels and greatly accelerated cardiac remodeling associated with normal aging compared with those on a normal diet. Chronic elevation of circulating Klotho because of global overexpression alleviated the cardiac remodeling induced by either high-phosphate diet or CKD. Regardless of the cause of Klotho deficiency, the extent of cardiac hypertrophy and fibrosis correlated tightly with plasma phosphate concentration and inversely with plasma Klotho concentration, even when adjusted for all other covariables. High-fibroblast growth factor-23 concentration positively correlated with cardiac remodeling in a Klotho-deficient state but not a Klotho-replete state. In vitro, Klotho inhibited TGF-b1-, angiotensin II-, or high phosphate-induced fibrosis and abolished TGF-b1-or angiotensin II-induced hypertrophy of cardiomyocytes. In conclusion, Klotho deficiency is a novel intermediate mediator of pathologic cardiac remodeling, and fibroblast growth factor-23 may contribute to cardiac remodeling in concert with Klotho deficiency in CKD, phosphotoxicity, and aging.

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Section: Discussionmentioning

confidence: 99%

Klotho and Phosphate Are Modulators of Pathologic Uremic Cardiac Remodeling

Hu¹,

Shi²,

Cho³

et al. 2015

Journal of the American Society of Nephrology

Self Cite

231

298

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“…Other mechanisms by which FGF‐23 could lead to adverse cardiovascular consequences include calcitriol deficiency, altered phosphorus homeostasis, systemic inflammation and oxidative stress, and sodium retention 31, 32, 33. Additionally, FGF‐23 may downregulate soluble α‐klotho,34 an enzyme with anti‐aging effects that was shown to protect the heart against cardiac hypertrophy and cardiac remodeling 35, 36. In a study by Reindl et al, FGF‐23 was significantly higher in patients who developed LV remodeling post ST‐segment–elevation myocardial infarction even after adjustment for biomarkers of myocardial necrosis, myocardial stress, and inflammation 37.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor‐23 and Heart Failure With Reduced Versus Preserved Ejection Fraction: MESA

Almahmoud

Soliman

Bertoni

et al. 2018

JAHA

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BackgroundHigher fibroblast growth factor‐23 (FGF‐23) levels are associated with incident heart failure (HF) in MESA (the Multiethnic Study of Atherosclerosis). FGF‐23 is also associated with left ventricular hypertrophy. Whether the FGF‐23 association with HF is similar for heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) is not well established.Methods and ResultsWe studied 6542 participants (mean age 62±10 years, 53% women, mean estimated glomerular filtration rate of 81±18 mL/min per 73 m2) from MESA who were free of cardiovascular disease at baseline (2000–2002). HF events were ascertained by an adjudication committee for a median follow‐up of 12.1 years. We classified HF events as HFrEF (ejection fraction [EF] <50%) or HFpEF [EF] ≥50%) at the time of diagnosis. Cox proportional hazard regression was used to compute hazard ratios and 95% confidence intervals for the association between baseline serum FGF‐23 and incident HFrEF and HFpEF. A total of 134 events were classified as HFpEF, 151 HFrEF, and 49 unknown EF. Following imputation, 149 were classified as HFpEF, 176 HFrEF, and 291 participants had HF (34 participants had HFpEF then HFrEF). In the fully adjusted model, higher FGF‐23 levels were associated with incident HFpEF but not with HFrEF (hazard ratio 1.29, 95% confidence interval, 1.08–1.54) versus (hazard ratio 1.04, 95% confidence interval, 0.84–1.29) for each 20 pg/mL higher serum FGF‐23 concentration.Conclusions FGF‐23 association with HF is driven by the association with HFpEF but not with HFrEF in a population‐based cohort. Further studies are needed to determine the pathological mechanisms mediating this association.

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“…The recent report by Faul and coworkers (Faul et al, 2011) suggested that FGF23 may induce left ventricular hypertrophy by a direct, Klotho-independent action on cardiomyocytes. In contrast, Xie and coworkers (Xie et al, 2012) reported that Klotho may be cardioprotective by an FGF23-independent downregulation of stressinduced calcium channels.…”

Section: Introductionmentioning

confidence: 91%