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Rationale: Cardiac aging is an important contributing factor for heart failure, which affects a large population but remains poorly understood. Objective: The purpose of this study is to investigate whether Klotho plays a role in cardiac aging. Methods and Results: Heart function declined in old mice (24 months), as evidenced by decreases in fractional shortening, ejection fraction, and cardiac output. Heart size and weight, cardiomyocyte size, and cardiac fibrosis were increased in old mice, indicating that aging causes cardiac hypertrophy and remodeling. Circulating Klotho levels were dramatically decreased in old mice, which prompted us to investigate whether the Klotho decline may cause heart aging. We found that Klotho gene mutation (KL−/−) largely decreased serum klotho levels and impaired heart function. Interestingly, supplement of exogenous secreted Klotho prevented heart failure, hypertrophy, and remodeling in both old mice and KL (−/−) mice. Secreted Klotho treatment inhibited excessive cardiac oxidative stress, senescence and apoptosis in old mice and KL (−/−) mice. Serum phosphate levels in KL (−/−) mice were kept in the normal range, suggesting that Klotho deficiency-induced heart aging is independent of phosphate metabolism. Mechanistically, Klotho deficiency suppressed GR (glutathione reductase) expression and activity in the heart via inhibition of transcription factor Nrf2 (nuclear factor-erythroid 2 p45-related factor 2). Furthermore, cardiac-specific overexpression of GR prevented excessive oxidative stress, apoptosis, and heart failure in both old and KL (−/−) mice. Conclusions: Klotho deficiency causes cardiac aging via impairing the Nrf2-GR pathway. Supplement of exogenous secreted Klotho represents a promising therapeutic strategy for aging-associated cardiomyopathy and heart failure.

Background: Aging is a well-known contributing factor for heart failure, which is the leading cause of death world-wide. However, the underlying mechanisms of heart aging are less clear. Methods and Results: We found that the overall heart size, heart weight, and cardiomyocyte size were increased in aged mice (24 months). Cardiac fibrosis was also found in old mice. Therefore, aging induced cardiac hypertrophy and remodeling. Concomitantly, heart function declined significantly in aged mice, as evidenced by decreases in fraction shorting, ejection fraction, left ventricular stroke volume, and cardiac output. Renal and circulating Klotho levels were dramatically decreased, suggesting that there may be association between a decrease in Klotho and heart failure in aged mice. Using Klotho mutant homozygous (KL-/-) mice, we found that Klotho deficiency caused cardiac hypertrophy and heart failure. Interestingly, treatment with secreted Klotho prevented cardiac hypertrophy, remodeling and heart failure in aged mice and KL (-/-) mice. Secreted Klotho treatment attenuated excessive cardiac oxidative stress and apoptosis in old mice and KL (-/-) mice. In this study, all KL (-/-) mice were fed with low-phosphate diet which maintained serum phosphate at the normal level, suggesting that the cardioprotective effects of secreted Klotho were independent of phosphate metabolism. Mechanistically, Klotho deficiency suppressed glutathione reductase (GR) expression and activity in the heart through downregulation of a transcription factor Nrf2. Furthermore, heart-specific overexpression of GR prevented aging- and Klotho deficiency-induced heart failure, excessive cardiac oxidative stress and apoptosis in old mice and KL (-/-) mice. Conclusions: Klotho deficiency plays an important role in aging-related heart failure. Secreted Klotho protects against heart aging via activation of glutathione reductase which attenuates cardiac oxidative stress, apoptosis and fibrosis.

Abstract —The attraction, binding, and entry of monocytes into the vessel wall play an important role in atherogenesis. We have previously shown that minimally oxidized/modified LDL (MM-LDL), a pathogenically relevant lipoprotein, can activate human aortic endothelial cells (HAECs) to produce monocyte chemotactic activators. In the present study, we demonstrate that MM-LDL and oxidation products of 1-palmitoyl-2-arachidonyl- sn -glycero-3-phosphocholine (PAPC) activate endothelial cells to synthesize monocyte chemotactic protein-1 (MCP-1) and interleukin-8 (IL-8). Several lines of evidence suggest that this activation is mediated by the lipid-dependent transcription factor peroxisome proliferator-activated receptor α (PPARα), the most abundant member of the PPAR family in HAECs. Treatment of transfected CV-1 cells demonstrated activation of the PPARα ligand-binding domain by MM-LDL, Ox-PAPC, or its component phospholipids, 1-palmitoyl-2-oxovalaroyl- sn -glycero-phosphocholine and 1-palmitoyl-2-glutaroyl- sn -glycero-phosphocholine; these lipids also activated a consensus peroxisome proliferator-activated receptor response element (PPRE) in transfected HAECs. Furthermore, activation of PPARα with synthetic ligand Wy14,643 stimulates the synthesis of IL-8 and MCP-1 by HAECs. By contrast, troglitazone, a PPARγ agonist, decreased the levels of IL-8 and MCP-1. Finally, we demonstrate that unlike wild-type endothelial cells, endothelial cells derived from PPARα null mice do not produce MCP-1/JE in response to Ox-PAPC and MM-LDL. Together, these data demonstrate a proinflammatory role for PPARα in mediation of the activation of endothelial cells to produce monocyte chemotactic activity in response to oxidized phospholipids and lipoproteins.