Mammalian sterile 20 like kinase 1 (Mst1) is one of the most prominently activated serine/threonine kinases when cardiomyocytes (CMs) undergo apoptosis. Mst1 plays an important role in mediating ischemia/reperfusion (I/R) injury and cardiac dysfunction after myocardial infarction (MI). Mst1 also inhibits compensatory hypertrophy, thereby initiating a vicious cycle consisting of wall thinning, increases in wall stress, and chamber dilation. Despite the importance of Mst1 in regulating growth and death of CMs, how Mst1 is activated by pathological insults and how Mst1 mediates myocardial cell death are poorly understood. Genetic studies in Drosophila have suggested that hippo, a homolog of mammalian Mst1, belongs to a signaling cascade termed the hippo pathway, which plays an important role in regulating organ size through stimulation of apoptosis and suppression of cell proliferation. The cellular function of the hippo pathway appears to be conserved from Drosophila to mammals, indicating its fundamental importance. Our long-term hypothesis is that the mammalian hippo pathway regulates growth and death of CMs. In this study, we hypothesize: 1. K-Ras is activated by I/R through oxidation and serves as a critical upstream regulator of Mst1 at mitochondria. K-Ras, Rassf1A and Mst1 form a complex and phosphorylate mitochondrial proteins, including Bcl-xL, thereby stimulating apoptosis. 2. The function of the Rassf1A-Mst1 pathway during I/R is cell type- dependent, and activation of the Rassf1A-Mst1 pathway in cardiac fibroblasts could be salutary for the heart during I/R through suppression of cytokines. 3. Decreases in the nuclear localization of YAP promote myocardial injury, whereas restoration of YAP expression promotes myocardial survival and regeneration during chronic MI. We will address these issues using genetically altered (gain and loss of function) mouse models, as well as proteomic approaches. Addressing these issues will allow us to elucidate the role of signaling mechanisms both upstream and downstream of Mst1 in mediating survival, death and growth of CMs in response to I/R. The knowledge obtained from these experiments should be useful for developing specific strategies to limit myocardial injury in patients with ischemic heart disease.
Despite recent advancement in medical treatment, the mortality caused by ischemic heart disease remains high and myocardial injury caused by acute heart attack is a significant cause of heart failure. This study will investigate the role of the mammalian hippo pathway in controlling cell death in the heart during and after acute heart attack. Our study may lead to the development of a novel treatment for ischemic heart disease.
|Ikeda, Shohei; Mizushima, Wataru; Sciarretta, Sebastiano et al. (2018) Hippo Deficiency Leads to Cardiac Dysfunction Accompanied by Cardiomyocyte De-Differentiation During Pressure Overload. Circ Res :|
|Sciarretta, Sebastiano; De Falco, Elena; Frati, Giacomo et al. (2017) How to be young at heart? miR-22 as a potential therapeutic target to boost autophagy and protect the old myocardium. Ann Transl Med 5:52|
|Nagarajan, Narayani; Oka, Shinichi; Sadoshima, Junichi (2017) Modulation of signaling mechanisms in the heart by thioredoxin 1. Free Radic Biol Med 109:125-131|
|Sadoshima, Junichi (2017) Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School. Circ Res 121:1127-1129|
|Sadoshima, Junichi; Tomoike, Hitonobu (2017) What Should We Learn From the Recent Decline of Basic Cardiovascular Science in Japan? Circ Res 121:314-316|
|Oka, Shin-Ichi; Hirata, Tsuyoshi; Suzuki, Wataru et al. (2017) Thioredoxin-1 maintains mechanistic target of rapamycin (mTOR) function during oxidative stress in cardiomyocytes. J Biol Chem 292:18988-19000|
|Saito, Toshiro; Sadoshima, Junichi (2017) Unexpected Functional Consequences of the Loss of the Autophagy-Related Conjugation System. Circ Res 120:610-612|
|Mizushima, Wataru; Sadoshima, Junichi (2017) BAG3 plays a central role in proteostasis in the heart. J Clin Invest 127:2900-2903|
|Matsuda, Takahisa; Zhai, Peiyong; Sciarretta, Sebastiano et al. (2016) NF2 Activates Hippo Signaling and Promotes Ischemia/Reperfusion Injury in the Heart. Circ Res 119:596-606|
|Matsushima, Shouji; Zablocki, Daniela; Tsutsui, Hiroyuki et al. (2016) Poldip2 negatively regulates matrix synthesis at focal adhesions. J Mol Cell Cardiol 94:10-12|
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