PKG and mTOR signaling in Heart Disease

• Applicant: Dr. Christian Oeing
• Subject Area: Cardiology, Angiology ; Cell Biology
• Term: from 2017 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 391697507

Heart failure is still a major cause of death worldwide despite great advances in medical therapy. Heart failure affects about 6 million people only in the United States of America leading to 350,000 deaths each year. To understand the pathomechanism is key to improve heart failure therapy. To decipher the interaction of mTOR and PKG can be essential for the development of future therapeutic approaches of heart failure.David Kass’ group shows for the first time that PKG stimulates autophagy by inhibiting mTOR activity, improving heart function and blocking maladaptive responses to hormonal and overload stress. This requires PKG phosphorylation (activation) of tuberin (TSC2), a principal negative modulator of mTOR. We find PKG blunts mTOR by activation of TSC2 at a novel but highly conserved site (S1365), enhancing autophagy and countering pathological stress remodeling. As revealed in unpublished preliminary data, this new mechanism is exciting because its impact is substantial when mTOR is being activated, but not under resting conditions. Myocytes subjected to hormone stress while expressing a phospho-silenced TSC2 mutant (S1365A) have greater mTOR activation, hypertrophy, and less autophagy that is not reversible by PKG activation. In a newly made S1365A knock-in mouse, we find normal heart function at rest, but rapid maladaptation to pressure overload with early lethality. We propose that PKG control over mTOR via TSC2 is a dominant mechanism underlying PKG brake-like activity to counter pathological growth and improve metabolism. In summary, PKG activation suppresses mTOR signaling and this action requires TSC2-S1365 phosphorylation. Additionally, a TSC2 S1365A mutation worsens both cellular and organ responses to stress, with reduced autophagy and worsened hypertrophy.In this project, we therefore employ a multi-scale approach to address major basic and translational questions in heart failure in 2 specific objectives: first, we want to determine the specificity of PKG for phosphorylating TSC2-S1365, and second, we plan to determine the relation of PKG activity to pS1365 in heart disease. This can be crucial to develop new therapeutic strategies for the diseased heart which remains a major leading cause of death worldwide.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. David A. Kass