Modulating fatty acid metabolism in pathological cardiac hypertrophy

• Applicant: Dr. Julia Ritterhoff
• Subject Area: Cardiology, Angiology
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 314284740

Alterations in cardiac metabolism are among the earliest changes occurring in cardiac hypertrophy. The net effect of an altered metabolic phenotype consists of reduced cardiac fatty oxidation, increased glycolysis and glucose oxidation, and rigidity of the metabolic response to changes in workload. However, whether this metabolic shift is an adaptive mechanism that protects the heart or a maladaptive process that accelerates structural and functional derangement remains unclear. Additionally, fluctuating metabolite levels have been brought into the focus, which are supposed to directly contribute to remodeling events, e.g. by influencing epigenetic modifications. Thus, identification of molecular factors that beneficially influence cardiac metabolism early on might enable the design of targeted therapeutic interventions to prevent disease progression. Increasing fatty acid oxidation by cardiac-specific deletion of acetyl-CoA carboxlyase (ACC2) has been shown to sustain fatty acid oxidation and preserve cardiac function in cardiac hypertrophy. However, the underlying molecular mechanism of this effect is still undiscovered.The central hypothesis of the present proposal is that sustaining fatty acid oxidation during chronic stress protects the heart against pathological hypertrophy. In particular, this proposal aims to investigate two possible mechanisms by which modulating fatty acid oxidation acts beneficial: 1) by reducing the reliance on glucose and by preventing the mismatch of fatty acid supply and its oxidation and 2) by changing certain metabolite levels that mediate epigenetic changes as e.g. histone acetylation. Finally, the ultimate goal of this proposal is to translate these finding into an in vivo model to determine if increasing fatty acid oxidation in established pathological hypertrophy can prevent cardiac deterioration or improve cardiac function. The resulting findings will not only improve our understanding on how modulation of cardiac metabolism contributes to disease progression but they will also help to develop novel metabolic therapies for cardiac diseases.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Rong Tian