Role of soluble adenylyl cyclase in ischemia-reperfusion-induced brain injury

• Applicant: Privatdozent Dr. Yury Ladilov
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2010 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 165505620

• Final Report Year: 2015

Final Report Abstract

The results of the project demonstrate the novel role of sAC in cell death and growth (for review see publication 6 above). First, investigations with cultured neurons and cardiomyocytes provide convincing evidences that sAC significantly contributes to the hypoxia/anoxia and reoxygenation induced apoptotic cell death. Inhibition of sAC rescued the jeopardized neurons and cardiomyocytes. Although the mechanistic side of the sAC action is still incompletely understood, the involvement of mitochondrial pathway of apoptosis, and particularly sAC-PKA-dependent Bax phosphorylation, has been found. Second, aside of hypoxia/anoxia, sAC contribute to the smooth muscle cells apoptosis induced either by direct treatment with ROS or with oxysterols. Third, our findings demonstrate that sAC controls cell proliferation and radioresistance. sAC promotes cell growth and survival due to activation of EPAC-BRaf-ERK signaling. Therefore, sAC, as an alternative, intracellular localized source of cAMP, may play a controversial role regarding cell survival. The further investigation of the mechanistic part of sAC action is required to reveal the causes for the controversy. Nevertheless, these initial studies provide the basis for the development of new strategies for the treatment of diseases arising from the dysregulation of cell growth, such as cancer and cardiac hypertrophy, or from enhanced cell death, including neurodegenerative and ischemic diseases.

Publications

• Type 10 adenylyl cyclase mediates mitochondrial Bax translocation and apoptosis of adult rat cardiomyocytes under simulated ischaemia/reperfusion. Cardiovasc Res. 2012 Feb 1; 93(2):340-9
  Appukuttan, Avinash; Kasseckert, Sascha A.; Micoogullari, Mustafa; Flacke, Jan-Paul; Kumar, Sanjeev; Woste, Alexandra; Abdallah, Yaser; Pott, Lutz; Reusch, H. Peter & Ladilov, Yury
  
• Oxysterol-induced apoptosis of smooth muscle cells is under the control of a soluble adenylyl cyclase. Cardiovasc Res. 2013 Sep 1; 99(4):734-42
  Appukuttan, Avinash; Kasseckert, Sascha Andreas; Kumar, Sanjeev; Reusch, H. Peter & Ladilov, Yury
  
• Type 10 soluble adenylyl cyclase is overexpressed in prostate carcinoma and controls proliferation of prostate cancer cells. J Biol Chem. 2013 Feb 1; 288(5):3126-35
  Flacke, Jan-Paul; Flacke, Hanna; Appukuttan, Avinash; Palisaar, Rein-Jüri; Noldus, Joachim; Robinson, Brian D.; Reusch, H. Peter; Zippin, Jonathan H. & Ladilov, Yury
  
• Inhibition of soluble adenylyl cyclase increases the radiosensitivity of prostate cancer cells. Biochim Biophys Acta. 2014; 1842:2656-63
  Appukuttan, Avinash; Flacke, Jan-Paul; Flacke, Hanna; Posadowsky, Alexandra; Reusch, H. Peter & Ladilov, Yury
  
• Role of soluble adenylyl cyclase in cell death and growth. Biochim Biophys Acta. 2014; 1842:2646-2655
  Ladilov, Yury & Appukuttan, Avinash
  
• Suppression of soluble adenylyl cyclase protects smooth muscle cells against oxidative stress-induced apoptosis. Apoptosis. 2014 Jul;19(7):1069-79
  Kumar, Sanjeev; Appukuttan, Avinash; Maghnouj, Abdelouahid; Hahn, Stephan; Peter Reusch, H. & Ladilov, Yury