CXL 1020 is an experimental drug that is being investigated as a treatment for acute decompensated heart failure. CXL 1020 functions as a nitroxyl donor; nitroxyl is the reduced, protonated version of nitric oxide. [1] Nitroxyl is capable of enhancing left ventricular contractility without increasing heart rate by modifying normal Ca2+ cycling through the sarcoplasmic reticulum [2] as well as increasing the sensitivity of cardiac myofilaments to Ca2+. [3]
Acute decompensated heart failure
Patients with acute decompensated heart failure have diminished left ventricular systolic and/or diastolic functioning. [4] Impaired ventricular function can be a consequence of decreased sarcoplasmic reticulum Ca2+ cycling and a corresponding decline in cardiomyocyte contraction. [2] Reduced ventricular functioning limits the ability of the ventricles to fill with blood and pump blood to the rest of the body.
Sarcoplasmic reticulum Ca2+ Cycling
There are two mechanisms through which CXL 1020 is able to enhance the movement of Ca2+ in and out of the sarcoplasmic reticulum. Sarcoplasmic reticulum CaATPase (SERCA) is an energy-dependent ion pump found the sarcoplasmic reticulum of cardiac myocytes that is responsible for transporting Ca2+ within the cytosol back in to the lumen of the sarcoplasmic reticulum. [2] The nitroxyl group that is donated by CXL 1020 initiates glutathiolation of SERCA at the cysteine 674 site, which in turn activates ATP-dependent Ca2+ transport. [5] Therefore, stimulation of SERCA leads to accelerated uptake of Ca2+ from the cytosol of the cardiac myocyte.
Secondly, the nitroxyl group from CXL 1020 interacts with ryanodine receptors (RyR), specifically RyR2, which is the predominant form found in cardiac tissue. [6] Ryanodine receptors are located within the membrane of the sarcoplasmic reticulum and function to release Ca2+ required for myofilament activation (Guyton, 2006). Nitroxyl interacts with RyR2 to increase the probability of Ryanodine receptor opening, thereby enhancing Ca2+ release from the sarcoplasmic reticulum. It is thought that nitroxyl modifies RyR2 function through its interaction with thiol groups present in the receptor, although the exact mechanism is unknown. [6]
Cardiac myocyte contractility
Nitroxyl has also been shown to increase the sensitivity to cardiac myocytes to Ca2+, which in turn enhances the force of contraction. Its hypothesized that nitroxyl interacts with thiol groups present in myofilament proteins to increase the maximal Ca2+ activated force of the myofilament, although the exact effect of nitroxyl on the myofilament is unknown. [3]
References
- ^ Del Rio, Carlos; Yukie Ueyama; Robert L. Hamlin; John Reardon; Reza Mazhari (April 2011). "CXL-1020, A Novel Hno Donor, Decreases Myocardial Loading and Enhances Load-Independent Lusitropy and Inotropy Via A ?-Ar/Ace Independent Mechanism". JACC. 57 (17): E326. doi: 10.1016/s0735-1097(11)60326-4.
- ^ a b c Kohr, Mark; Nina Kaludercic; Carlo Tocchetti; Wei Dong Gao; David Kass; Paul Janssen; Nazareno Paolocci; Mark Ziolo (March 2011). "Nitroxyl enhances myocyte Ca2+ transients by exclusively targeting SR Ca2+-cycling". Frontiers in Bioscience. E2 (2): 614–626. doi: 10.2741/e118. PMC 3057191. PMID 20036906.
- ^ a b Dai, Tieying; Ye Tian; Carlo Tocchetti; Tatsuo Katori; Anne Murphy; David Kass; Nazareno Paolocci; Wei Dong Gao (2007). "Nitroxyl increases force development in rat cardiac muscle". Journal of Physiology. 580 (3): 951–960. doi: 10.1113/jphysiol.2007.129254. PMC 2075441. PMID 17331988.
- ^ Wang, Mengjun; Reza Mazhari; Itamar Ilsar; Alice Wang; Michael Sabbah; Hani Sabbah (2009). "Intravenous Infusion of CXL-1020, a Novel Nitroxyl (HNO) Donor, Improves Left Ventricular Systolic and Diastolic Function in Dogs with Advanced Heart Failure". Circulation. 120: S582.
- ^ Lancel, Steve; Jingmei Zhang; Alicia Evangelista; Mario Trucillo; XiaoYong Tong; Deborah Siwik; Richard Cohen; Wilson Colucci (2009). "Nitroxyl Activates SERCA in Cardiac Myocytes via Glutathiolation of Cysteine 674". Circulation Research. 104 (6): 720–723. doi: 10.1161/circresaha.108.188441. PMC 3046805. PMID 19265039.
- ^ a b Tocchetti, Carlo; Wang Wang; Jeffrey Froehlich; Sabine Huke; Miguel Aon; Gerald Wilson; Giulietta Di Benedetto; Brian O'Rourke; Wei Dong Gao; David Wink; John Toscano; Manuela Zaccolo; Donald Bers; Hector Valdivia; Heping Cheng; David Kass; Nazareno Paolocci (2007). "Nitroxyl Improves Cellular Heart Function by Directly Enhancing Cardiac Sarcoplasmic Reticulum Ca 2+ Cycling". Circulation Research. 100 (1): 96–104. doi: 10.1161/01.res.0000253904.53601.c9. PMC 2769513. PMID 17138943.
CXL 1020 is an experimental drug that is being investigated as a treatment for acute decompensated heart failure. CXL 1020 functions as a nitroxyl donor; nitroxyl is the reduced, protonated version of nitric oxide. [1] Nitroxyl is capable of enhancing left ventricular contractility without increasing heart rate by modifying normal Ca2+ cycling through the sarcoplasmic reticulum [2] as well as increasing the sensitivity of cardiac myofilaments to Ca2+. [3]
Acute decompensated heart failure
Patients with acute decompensated heart failure have diminished left ventricular systolic and/or diastolic functioning. [4] Impaired ventricular function can be a consequence of decreased sarcoplasmic reticulum Ca2+ cycling and a corresponding decline in cardiomyocyte contraction. [2] Reduced ventricular functioning limits the ability of the ventricles to fill with blood and pump blood to the rest of the body.
Sarcoplasmic reticulum Ca2+ Cycling
There are two mechanisms through which CXL 1020 is able to enhance the movement of Ca2+ in and out of the sarcoplasmic reticulum. Sarcoplasmic reticulum CaATPase (SERCA) is an energy-dependent ion pump found the sarcoplasmic reticulum of cardiac myocytes that is responsible for transporting Ca2+ within the cytosol back in to the lumen of the sarcoplasmic reticulum. [2] The nitroxyl group that is donated by CXL 1020 initiates glutathiolation of SERCA at the cysteine 674 site, which in turn activates ATP-dependent Ca2+ transport. [5] Therefore, stimulation of SERCA leads to accelerated uptake of Ca2+ from the cytosol of the cardiac myocyte.
Secondly, the nitroxyl group from CXL 1020 interacts with ryanodine receptors (RyR), specifically RyR2, which is the predominant form found in cardiac tissue. [6] Ryanodine receptors are located within the membrane of the sarcoplasmic reticulum and function to release Ca2+ required for myofilament activation (Guyton, 2006). Nitroxyl interacts with RyR2 to increase the probability of Ryanodine receptor opening, thereby enhancing Ca2+ release from the sarcoplasmic reticulum. It is thought that nitroxyl modifies RyR2 function through its interaction with thiol groups present in the receptor, although the exact mechanism is unknown. [6]
Cardiac myocyte contractility
Nitroxyl has also been shown to increase the sensitivity to cardiac myocytes to Ca2+, which in turn enhances the force of contraction. Its hypothesized that nitroxyl interacts with thiol groups present in myofilament proteins to increase the maximal Ca2+ activated force of the myofilament, although the exact effect of nitroxyl on the myofilament is unknown. [3]
References
- ^ Del Rio, Carlos; Yukie Ueyama; Robert L. Hamlin; John Reardon; Reza Mazhari (April 2011). "CXL-1020, A Novel Hno Donor, Decreases Myocardial Loading and Enhances Load-Independent Lusitropy and Inotropy Via A ?-Ar/Ace Independent Mechanism". JACC. 57 (17): E326. doi: 10.1016/s0735-1097(11)60326-4.
- ^ a b c Kohr, Mark; Nina Kaludercic; Carlo Tocchetti; Wei Dong Gao; David Kass; Paul Janssen; Nazareno Paolocci; Mark Ziolo (March 2011). "Nitroxyl enhances myocyte Ca2+ transients by exclusively targeting SR Ca2+-cycling". Frontiers in Bioscience. E2 (2): 614–626. doi: 10.2741/e118. PMC 3057191. PMID 20036906.
- ^ a b Dai, Tieying; Ye Tian; Carlo Tocchetti; Tatsuo Katori; Anne Murphy; David Kass; Nazareno Paolocci; Wei Dong Gao (2007). "Nitroxyl increases force development in rat cardiac muscle". Journal of Physiology. 580 (3): 951–960. doi: 10.1113/jphysiol.2007.129254. PMC 2075441. PMID 17331988.
- ^ Wang, Mengjun; Reza Mazhari; Itamar Ilsar; Alice Wang; Michael Sabbah; Hani Sabbah (2009). "Intravenous Infusion of CXL-1020, a Novel Nitroxyl (HNO) Donor, Improves Left Ventricular Systolic and Diastolic Function in Dogs with Advanced Heart Failure". Circulation. 120: S582.
- ^ Lancel, Steve; Jingmei Zhang; Alicia Evangelista; Mario Trucillo; XiaoYong Tong; Deborah Siwik; Richard Cohen; Wilson Colucci (2009). "Nitroxyl Activates SERCA in Cardiac Myocytes via Glutathiolation of Cysteine 674". Circulation Research. 104 (6): 720–723. doi: 10.1161/circresaha.108.188441. PMC 3046805. PMID 19265039.
- ^ a b Tocchetti, Carlo; Wang Wang; Jeffrey Froehlich; Sabine Huke; Miguel Aon; Gerald Wilson; Giulietta Di Benedetto; Brian O'Rourke; Wei Dong Gao; David Wink; John Toscano; Manuela Zaccolo; Donald Bers; Hector Valdivia; Heping Cheng; David Kass; Nazareno Paolocci (2007). "Nitroxyl Improves Cellular Heart Function by Directly Enhancing Cardiac Sarcoplasmic Reticulum Ca 2+ Cycling". Circulation Research. 100 (1): 96–104. doi: 10.1161/01.res.0000253904.53601.c9. PMC 2769513. PMID 17138943.