Rottlerin Explained

Rottlerin (mallotoxin) is a polyphenol natural product isolated from the Asian tree Mallotus philippensis. Rottlerin displays a complex spectrum of pharmacology.[1]

Effects

Uncoupler of oxidative phosphorylation

Rottlerin has been shown to be an uncoupler of mitochondrial oxidative phosphorylation.[2] [3] [4]

Potassium channel opener

Rottlerin is a potent large conductance potassium channel (BKCa++) opener.[5] BKCa++ is found in the inner mitochondrial membrane of cardiomyocytes.[6] Opening these channels is beneficial for post-ischemic changes in vasodilation.[7] Other BKCa++ channel openers are reported to limit the mitochondrial calcium overload due to ischemia.[8] [9] Rottlerin is also capable of reducing oxygen radical formation.[1]

Other BKCa++ channel openers (NS1619, NS11021 and DiCl-DHAA) have been reported to have cardio-protective effects after ischemic-reperfusion injury.[9] [10] [11] There were reductions in mitochondrial Ca++ overload, mitochondrial depolarization, increased cell viability and improved function in the whole heart.[9] [10] [11]

Mallotoxin is also a hERG potassium channel activator.[12]

Role in cardioplegia reperfusion

Clements et al.[5] reported that rottlerin improves the recovery of isolated rat hearts perfused with buffer after cold cardioplegic arrest. A majority of patients recover but some develop a cardiac low-output syndrome attributable in part to depressed left ventricular or atrial contractility, which increases chance of death.[5]

Contractility and vascular effects

Rottlerin increases in isolated heart contractility independent of its vascular effects, as well as enhanced perfusion through vasomotor activity. The activation of BKCa++ channels by rottlerin relaxes coronary smooth muscle and improves myocardial perfusion after cardioplegia.[5]

Myocardial stunning is associated with oxidant radical damage and calcium overload.[5] Contractile abnormalities can occur through oxidant-dependent damage and also through calcium overload in the mitochondria resulting in mitochondrial damage.[13] [14] [15] BKCa++ channels reside in the inner mitochondrial membrane[6] and their activation is proposed to increase K+ accumulation in mitochondria.[8] [9] This limits influx into mitochondria, reducing mitochondrial depolarization and permeability transition pore opening.[8] [9] This may result in less mitochondrial damage and therefore greater contractility since there is a decrease in apoptosis compared to no stimulation of BKCa++ channels.[5]

Akt activation

Rottlerin also enhances the cardioplegia-induced phosphorylation of Akt on the activation residue Thr308.[5] Akt activation modulates mitochondrial depolarization and the permeability transition pore.[16] [17] Clements et al.[5] found that Akt functions downstream of the BKCa++ channels and its activation is considered beneficial after ischemic-reperfusion injury. It is unclear what the specific role of Akt may play in modulating of myocardial function after rottlerin treatment of cardioplegia.[5] More research needs to be done to examine if Akt is necessary to improve cardiac function when rottlerin is administered.[5]

Antioxidant properties

The antioxidant properties of rottlerin have been demonstrated but it is unclear whether the effects are because of BKCa++ channel opening or an additional mechanism of rottlerin.[1] [5] [18] There was no oxygen dependent damage found by rottlerin in the study conducted by Clements et al.[5]

Ineffective PKCδ selective inhibitor

Rottlerin has been reported to be a PKCδ inhibitor.[19] PKCδ has been implicated in depressing cardiac function and cell death after ischemia-reperfusion injury as well as promoting vascular smooth muscle contraction and decreasing perfusion.[5] However, the role of rottlerin as a specific PKCδ inhibitor has been questioned. There have been several studies using rottlerin as a PKCδ selective inhibitor based on in vitro studies, but some studies showed it did not block PKCδ activity and did block other kinase and non-kinase proteins in vitro.[1] [20] [21] Rottlerin also uncouples mitochondria at high doses and results in depolarization of the mitochondrial membrane potential.[1] It was found to reduce ATP levels, activate 5'-AMP-activated protein kinase and affect mitochondrial production of reactive oxygen species (ROS).[1] [6] [22] It is difficult to say that rottlerin is a selective inhibitor of PKCδ since there are biological and biochemical processes that are PKCδ –independent that may affect outcomes.[1] [5] [6] [22] A proposed mechanism of why rottlerin was found to inhibit PKCδ is that it decreased ATP levels and can block PKCδ tyrosine phosphorylation and activation.[1]

Sources

The Kamala tree, also known as Mallotus philippensis, grows in Southeast Asia.[19] The fruit of this tree is covered with a red powder called kamala, and is used locally to make dye for textiles, syrup and used as an old remedy for tape-worm, because it has a laxative effect.[23] Other uses include afflictions with the skin, eye diseases, bronchitis, abdominal disease, and spleen enlargement but scientific evidence is not present.[24]

Notes and References

  1. Soltoff SP . Rottlerin: an inappropriate and ineffective inhibitor of PKCdelta . Trends in Pharmacological Sciences . 28 . 9 . 453–458 . September 2007 . 17692392 . 10.1016/j.tips.2007.07.003 .
  2. Soltoff SP . Rottlerin is a mitochondrial uncoupler that decreases cellular ATP levels and indirectly blocks protein kinase Cdelta tyrosine phosphorylation . The Journal of Biological Chemistry . 276 . 41 . 37986–37992 . October 2001 . 11498535 . 10.1074/jbc.M105073200 . free .
  3. Kayali AG, Austin DA, Webster NJ . Rottlerin inhibits insulin-stimulated glucose transport in 3T3-L1 adipocytes by uncoupling mitochondrial oxidative phosphorylation . Endocrinology . 143 . 10 . 3884–3896 . October 2002 . 12239100 . 10.1210/en.2002-220259 . free .
  4. Tillman DM, Izeradjene K, Szucs KS, Douglas L, Houghton JA . Rottlerin sensitizes colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via uncoupling of the mitochondria independent of protein kinase C . Cancer Research . 63 . 16 . 5118–5125 . August 2003 . 12941843 .
  5. Clements RT, Cordeiro B, Feng J, Bianchi C, Sellke FW . Rottlerin increases cardiac contractile performance and coronary perfusion through BKCa++ channel activation after cold cardioplegic arrest in isolated hearts . Circulation . 124 . 11 Suppl . S55–S61 . September 2011 . 21911819 . 3358121 . 10.1161/CIRCULATIONAHA.110.012112 .
  6. Zakharov SI, Morrow JP, Liu G, Yang L, Marx SO . Activation of the BK (SLO1) potassium channel by mallotoxin . The Journal of Biological Chemistry . 280 . 35 . 30882–30887 . September 2005 . 15998639 . 10.1074/jbc.M505302200 . free .
  7. Han JG, Yang Q, Yao XQ, Kwan YW, Shen B, He GW . Role of large-conductance calcium-activated potassium channels of coronary arteries in heart preservation . The Journal of Heart and Lung Transplantation . 28 . 10 . 1094–1101 . October 2009 . 19782293 . 10.1016/j.healun.2009.06.011 .
  8. Kang SH, Park WS, Kim N, Youm JB, Warda M, Ko JH, Ko EA, Han J . 6 . Mitochondrial Ca2+-activated K+ channels more efficiently reduce mitochondrial Ca2+ overload in rat ventricular myocytes . American Journal of Physiology. Heart and Circulatory Physiology . 293 . 1 . H307–H313 . July 2007 . 17351070 . 10.1152/ajpheart.00789.2006 .
  9. Sato T, Saito T, Saegusa N, Nakaya H . Mitochondrial Ca2+-activated K+ channels in cardiac myocytes: a mechanism of the cardioprotective effect and modulation by protein kinase A . Circulation . 111 . 2 . 198–203 . January 2005 . 15623543 . 10.1161/01.cir.0000151099.15706.b1 . 9912508 .
  10. Bentzen BH, Osadchii O, Jespersen T, Hansen RS, Olesen SP, Grunnet M . Activation of big conductance Ca(2+)-activated K (+) channels (BK) protects the heart against ischemia-reperfusion injury . Pflügers Archiv . 457 . 5 . 979–988 . March 2009 . 18762970 . 10.1007/s00424-008-0583-5 . 25090971 .
  11. Sakamoto K, Ohya S, Muraki K, Imaizumi Y . A novel opener of large-conductance Ca2+ -activated K+ (BK) channel reduces ischemic injury in rat cardiac myocytes by activating mitochondrial K(Ca) channel . Journal of Pharmacological Sciences . 108 . 1 . 135–139 . September 2008 . 18758135 . 10.1254/jphs.08150sc . free .
  12. Zeng H, Lozinskaya IM, Lin Z, Willette RN, Brooks DP, Xu X . Mallotoxin is a novel human ether-a-go-go-related gene (hERG) potassium channel activator . The Journal of Pharmacology and Experimental Therapeutics . 319 . 2 . 957–962 . November 2006 . 16928897 . 10.1124/jpet.106.110593 . 21096055 .
  13. Bolli R, Marbán E . Molecular and cellular mechanisms of myocardial stunning . Physiological Reviews . 79 . 2 . 609–634 . April 1999 . 10221990 . 10.1152/physrev.1999.79.2.609 . 18283833 .
  14. Kloner RA, Jennings RB . Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 2 . Circulation . 104 . 25 . 3158–3167 . December 2001 . 11748117 . 10.1161/hc5001.100039 . 52874593 .
  15. Kloner RA, Jennings RB . Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1 . Circulation . 104 . 24 . 2981–2989 . December 2001 . 11739316 . 10.1161/hc4801.100038 . free .
  16. Miura T, Tanno M, Sato T . Mitochondrial kinase signalling pathways in myocardial protection from ischaemia/reperfusion-induced necrosis . Cardiovascular Research . 88 . 1 . 7–15 . October 2010 . 20562423 . 10.1093/cvr/cvq206 . free .
  17. Halestrap AP, Clarke SJ, Khaliulin I . The role of mitochondria in protection of the heart by preconditioning . Biochimica et Biophysica Acta (BBA) - Bioenergetics . 1767 . 8 . 1007–1031 . August 2007 . 17631856 . 2212780 . 10.1016/j.bbabio.2007.05.008 .
  18. Heinen A, Aldakkak M, Stowe DF, Rhodes SS, Riess ML, Varadarajan SG, Camara AK . Reverse electron flow-induced ROS production is attenuated by activation of mitochondrial Ca2+-sensitive K+ channels . American Journal of Physiology. Heart and Circulatory Physiology . 293 . 3 . H1400–H1407 . September 2007 . 17513497 . 10.1152/ajpheart.00198.2007 . 20330939 .
  19. Gschwendt M, Müller HJ, Kielbassa K, Zang R, Kittstein W, Rincke G, Marks F . Rottlerin, a novel protein kinase inhibitor . Biochemical and Biophysical Research Communications . 199 . 1 . 93–98 . February 1994 . 8123051 . 10.1006/bbrc.1994.1199 .
  20. Davies SP, Reddy H, Caivano M, Cohen P . Specificity and mechanism of action of some commonly used protein kinase inhibitors . The Biochemical Journal . 351 . Pt 1 . 95–105 . October 2000 . 10998351 . 1221339 . 10.1042/0264-6021:3510095 .
  21. Soltoff SP . Rottlerin is a mitochondrial uncoupler that decreases cellular ATP levels and indirectly blocks protein kinase Cdelta tyrosine phosphorylation . The Journal of Biological Chemistry . 276 . 41 . 37986–37992 . October 2001 . 11498535 . 10.1074/jbc.M105073200 . free .
  22. Tapia JA, Jensen RT, García-Marín LJ . Rottlerin inhibits stimulated enzymatic secretion and several intracellular signaling transduction pathways in pancreatic acinar cells by a non-PKC-delta-dependent mechanism . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1763 . 1 . 25–38 . January 2006 . 16364465 . 10.1016/j.bbamcr.2005.10.007 .
  23. Rao VS, Seshadri TR . 1947 . Kamala dye as an anthelmintic . Proceedings of the Indian Academy of Sciences . 26 . 3. 178–181 . 10.1007/BF03170871 . 81455004 .
  24. Mitra R, Kapoor LD . Kamala--the national flower of India--its ancient history and uses in Indian medicine . Indian Journal of History of Science . 11 . 2 . 125–132 . November 1976 . 11610202 .

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