Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Wallner, M; Eaton, DM; Berretta, RM; Liesinger, L; Schittmayer, M; Gindlhuber, J; Wu, J; Jeong, MY; Lin, YH; Borghetti, G; Baker, ST; Zhao, H; Pfleger, J; Blass, S; Rainer, PP; von Lewinski, D; Bugger, H; Mohsin, S; Graier, WF; Zirlik, A; McKinsey, TA; Birner-Gruenberger, R; Wolfson, MR; Houser, SR.
HDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction.
Sci Transl Med. 2020; 12(525):
Doi: 10.1126/scitranslmed.aay7205
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- Führende Autor*innen der Med Uni Graz
- Wallner Markus
- Co-Autor*innen der Med Uni Graz
- Birner-Grünberger Ruth
- Blass Sandra
- Bugger Heiko Matthias
- Gindlhuber Jürgen
- Graier Wolfgang
- Liesinger Laura
- Rainer Peter
- Schittmayer-Schantl Matthias
- von Lewinski Dirk
- Zirlik Andreas
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- Abstract:
- Heart failure with preserved ejection fraction (HFpEF) is a major health problem without effective therapies. This study assessed the effects of histone deacetylase (HDAC) inhibition on cardiopulmonary structure, function, and metabolism in a large mammalian model of pressure overload recapitulating features of diastolic dysfunction common to human HFpEF. Male domestic short-hair felines (n = 31, aged 2 months) underwent a sham procedure (n = 10) or loose aortic banding (n = 21), resulting in slow-progressive pressure overload. Two months after banding, animals were treated daily with suberoylanilide hydroxamic acid (b + SAHA, 10 mg/kg, n = 8), a Food and Drug Administration-approved pan-HDAC inhibitor, or vehicle (b + veh, n = 8) for 2 months. Echocardiography at 4 months after banding revealed that b + SAHA animals had significantly reduced left ventricular hypertrophy (LVH) (P < 0.0001) and left atrium size (P < 0.0001) versus b + veh animals. Left ventricular (LV) end-diastolic pressure and mean pulmonary arterial pressure were significantly reduced in b + SAHA (P < 0.01) versus b + veh. SAHA increased myofibril relaxation ex vivo, which correlated with in vivo improvements of LV relaxation. Furthermore, SAHA treatment preserved lung structure, compliance, blood oxygenation, and reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar capillary stress failure. Acetylation proteomics revealed that SAHA altered lysine acetylation of mitochondrial metabolic enzymes. These results suggest that acetylation defects in hypertrophic stress can be reversed by HDAC inhibitors, with implications for improving cardiac structure and function in patients. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.