Abstract 14399: Novel Mechanisms of Diastolic Dysfunction in Cardiac Aging

Nastaran Daneshgar; Dao-Fu Dai

doi:10.1161/circ.146.suppl_1.14399

Byline: Nastaran Daneshgar, Univ of Iowa, Iowa City, IA; Dao-Fu Dai, Iowa City, IA Aging is associated with a progressive decline in cardiac diastolic function. Membranous ð-klotho, predominantly produced by the kidney, can be cleaved and form circulating ð-klotho, which acts as an anti-aging hormone. Echocardiography showed klotho deficiency in 20-24-month-old heterozygous klotho (KL+/-) mice aggravates left ventricular hypertrophy (LVH) and diastolic dysfunction (DD) compared with old wild type (OWT) littermates. Supplementation with ð-Klotho (0.1mg/kg/day. i.p) for 10 weeks significantly reduced LV mass and ameliorated DD in both OWT and OKL. The improvement in DD was confirmed by Millar catheter measurement of -dP/dt. To gain mechanistic insights, we performed unbiased acetylomics using Acetyl-lysine antibody enrichment, followed by Tandem mass tag proteomics analysis. We identified 1215 lysine acetylation sites (K-Ac) on >1000 cardiac proteins, of which 220 K-Ac sites were significantly hyperacetylated in OWT hearts. There were 63 Ac-K sites >2-fold hyperacetylated in aged hearts (OWT vs. YWT). The comparison of OKL to YWT augmented the number of Ac-K sites to 82. These sites include redox proteins, several metabolic and mitochondrial proteins involved in fatty acid and amino acid metabolism, and the TCA cycle. Several isoforms of myosin heavy chains (MHC) were also hyperacetylated at multiple sites. Some hyperacetylated MHC (e.g. K941) are predicted to alter the molecular structure and relaxation kinetics by Molecular Dynamic Simulation. In addition to delayed Ca2+ reuptake by myocardial sarcoplasmic reticulum ATPase (SERCA2a), decreased SERCA2a expression and increased acetylated SERCA2 in aged hearts, which was all corrected upon klotho supplementation, we found potential novel mechanisms of DD with hyperacetylation of MHC, concomitant with a decrease in Sirt1 deacetylase, in OWT mice that was aggravated in OKL, which was replenished upon klotho supplementation. Collectively, we demonstrated klotho deficiency aggravates cardiac aging phenotypes, associated with hyperacetylation of several cardiac proteins due to diminished Sirt1. Klotho supplementation rejuvenates several cardiac aging phenotypes, including regression of LVH and improvement of DD, in parallel with reversal of protein acetylation.

Abstract 14399: Novel Mechanisms of Diastolic Dysfunction in Cardiac Aging

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