Pathological hypertrophic growth of cardiac myocytes can lead to heart failure;inhibiting this growth can avert heart failure. While we have a good understanding of growth-activating processes in the heart, there is a gap in our understanding of growth-inhibiting processes. The objective of this proposal is to address this gap by examining the protein quantity and quality control (PQQC) system in the sarco/endoplasmic reticulum (SR/ER) of cardiac myocytes, which we have shown can moderate cardiac myocyte growth. This objective aligns with our long-term goal of defining innovative strategies for averting heart failure by reducing pathological hypertrophy. We found that a key member of the SR/ER PQQC system, the transcription factor, ATF6, decreases cardiac myocyte hypertrophy. ATF6, which is also cardioprotective, is an SR/ER transmembrane (TM) protein that senses growth signals. We showed that ATF6 induces the SR/ER TM E3 ubiquitin (Ub) ligase, synoviolin (Syvn1);SR/ER TM Ub ligases have not been studied in the heart. Surprisingly, Syvn1 did not affect global protein ubiquitination or degradation, but it decreased cardiac myocyte hypertrophy in response to growth stimuli. The hypothesis is that Syvn1 decreases toxic protein misfolding by targeting terminally misfolded proteins made in the SR/ER for degradation. Moreover, Syvn1 can target select signaling proteins for degradation, such as the cytosolic growth-promoting kinase, serum/glucocorticoid-regulated kinase 1, SGK1, and that these functions contribute to the ability of Syvn1 to moderate cardiac hypertrophy. The approach will use viral-mediated gene transfer to cultured cardiac myocytes and to mouse hearts, in vivo, to examine the effects of Syvn1 gain- and loss-of-function.
The specific aims are to examine the effects of Syvn1- gain- or loss-of-function on 1) cardiac hypertrophy, 2) the degradation of misfolded SR/ER proteins during cardiac myocyte hypertrophy, and 3) the level, location and activity of SGK1, and its impact on cardiac myocyte hypertrophy. The proposed studies are expected to show that, as a regulator of PQQC, Syvn1 contributes to balancing protein synthesis and protein folding capacity. These results will be significant because they will reveal novel mechanisms of inhibiting hypertrophy, and they will identify new targets for HF therapy. The proposed research is innovative because roles for the SR/ER PQQC and, specifically, SR/ER TM E3 Ub ligases in growth regulation have not been examined in any tissue.
The proposed project is relevant to public health and the NIH mission, because it addresses the pathological cardiac hypertrophy that often leads to heart failure, which, in the U.S., affects 6M people and causes 500,000 deaths/year. Current therapies treat the symptoms of heart failure, but do not cure the disease. The proposed research examines novel molecular mechanisms of attenuating hypertrophy, which is expected to reveal new targets for the future development of innovative therapies for reducing pathological hypertrophy, thus averting heart failure.
| Glembotski, Christopher C (2017) Expanding the Paracrine Hypothesis of Stem Cell-Mediated Repair in the Heart: When the Unconventional Becomes Conventional. Circ Res 120:772-774 |
| Jin, Jung-Kang; Blackwood, Erik A; Azizi, Khalid et al. (2017) ATF6 Decreases Myocardial Ischemia/Reperfusion Damage and Links ER Stress and Oxidative Stress Signaling Pathways in the Heart. Circ Res 120:862-875 |
| Glembotski, Christopher C (2015) Breaking down the COP9 Signalsome in the heart: how inactivating a protein ubiquitin ligase increases protein ubiquitylation and protects the heart. Circ Res 117:914-6 |
| Doroudgar, Shirin; Völkers, Mirko; Thuerauf, Donna J et al. (2015) Hrd1 and ER-Associated Protein Degradation, ERAD, are Critical Elements of the Adaptive ER Stress Response in Cardiac Myocytes. Circ Res 117:536-46 |
