|Chemical and physical data|
|Molar mass||516.53852 g/mol|
|3D model (JSmol)|
Uncoupler of oxidative phosphorylation
Potassium channel opener
Rottlerin is a potent large conductance potassium channel (BKCa++) opener. BKCa++ is found in the inner mitochondrial membrane of cardiomyocytes. Opening these channels is beneficial for post-ischemic changes in vasodilation. Other BKCa++ channel openers are reported to limit the mitochondrial calcium overload due to ischemia. Rottlerin is also capable of reducing oxygen radical formation.
Other BKCa++ channel openers (NS1619, NS11021 and DiCl-DHAA) have been reported to have cardio-protective effects after ischemic-reperfusion injury. There were reductions in mitochondrial Ca++ overload, mitochondrial depolarization, increased cell viability and improved function in the whole heart.
Role in cardioplegia reperfusion
Clements et al. 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.
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.
Myocardial stunning is associated with oxidant radical damage and calcium overload. Contractile abnormalities can occur through oxidant-dependent damage and also through calcium overload in the mitochondria resulting in mitochondrial damage. BKCa++ channels reside in the inner mitochondrial membrane and their activation is proposed to increase K+ accumulation in mitochondria. This limits Ca2+ influx into mitochondria, reducing mitochondrial depolarization and permeability transition pore opening. 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.
Rottlerin also enhances the cardioplegia-induced phosphorylation of Akt on the activation residue Thr308. Akt activation modulates mitochondrial depolarization and the permeability transition pore. Clements et al. 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. More research needs to be done to examine if Akt is necessary to improve cardiac function when rottlerin is administered.
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. There was no oxygen dependent damage found by rottlerin in the study conducted by Clements et al.
Ineffective PKCδ selective inhibitor
Rottlerin has been reported to be a PKCδ inhibitor. 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. 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. Rottlerin also uncouples mitochondria at high doses and results in depolarization of the mitochondrial membrane potential. It was found to reduce ATP levels, activate 5'-AMP-activated protein kinase and affect mitochondrial production of reactive oxygen species (ROS). 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. 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.
The Kamala tree, also known as Mallotus philippensis, grows in Southeast Asia. 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. Other uses include afflictions with the skin, eye diseases, bronchitis, abdominal disease, and spleen enlargement but scientific evidence is not present.
- Soltoff SP (Sep 2007). "Rottlerin: an inappropriate and ineffective inhibitor of PKCdelta". Trends in Pharmacological Sciences. 28 (9): 453–8. doi:10.1016/j.tips.2007.07.003. PMID 17692392.
- Soltoff SP (Oct 2001). "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): 37986–92. doi:10.1074/jbc.M105073200. PMID 11498535.
- Kayali AG, Austin DA, Webster NJ (Oct 2002). "Rottlerin inhibits insulin-stimulated glucose transport in 3T3-L1 adipocytes by uncoupling mitochondrial oxidative phosphorylation". Endocrinology. 143 (10): 3884–96. doi:10.1210/en.2002-220259. PMID 12239100.
- Tillman DM, Izeradjene K, Szucs KS, Douglas L, Houghton JA (Aug 2003). "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): 5118–25. PMID 12941843.
- 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 2011 Sep 13; 124(11 Suppl):S55-61
- Zakharov SI, Morrow JP, Liu G, Yang L, Marx SO. Activation of the BK (SLO1) potassium channel by mallotoxin" J Biol Chem 2005;280: 30882–30887
- Han, JG; Yang, Q; Yao, XQ; Kwan, YW; Shen, B; He, GW (2009). "Role of large-conductance calcium-activated potassium channels of coronary arteries in heart preservation". J Heart Lung Transplant. 28: 1094–1101. doi:10.1016/j.healun.2009.06.011.
- Kang SH, Park WS, Kim N, Youm JB, Warda M, Ko JH, Ko EA, Han J. "Mitochondrial Ca2+-activated K+ channels more efficiently reduce mitochondrial Ca2+ overload in rat ventricular myocytes" Am J Physiol Heart Circ Physiol 2007;293:H307–H313
- Sato, T; Saito, T; Saegusa, N; Nakaya, H (2005). "Mitochondrial Ca2+-activated K+ channels in cardiac myocytes: a mechanism of the cardioprotective effect and modulation by protein kinase A". Circulation. 111: 198–203. doi:10.1161/01.cir.0000151099.15706.b1. PMID 15623543.
- Bentzen, BH; Osadchii, O; Jespersen, T; Hansen, RS; Olesen, SP; Grunnet, M (2009). "Activation of big conductance Ca(2 )-activated K ( ) channels (BK) protects the heart against ischemia-reperfusion injury". Pflugers Arch. 457: 979–988. doi:10.1007/s00424-008-0583-5.
- Sakamoto, K; Ohya, S; Muraki, K; Imaizumi, YA (2008). "Novel opener of largeconductance Ca2 -activated K (BK) channel reduces ischemic injury in rat cardiac myocytes by activating mitochondrial K(Ca) channel". J Pharmacol Sci. 108: 135–139. doi:10.1254/jphs.08150sc.
- Bolli, R; Marban, E (1999). "Molecular and cellular mechanisms of myocardial stunning". Physiol. Rev. 79: 609–634. doi:10.1152/physrev.19184.108.40.2069.
- Kloner, RA; Jennings, RB (2001). "Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 2". Circulation. 104: 3158–3167. doi:10.1161/hc5001.100039.
- Kloner, RA; Jennings, RB (2001). "Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1". Circulation. 104: 2981–2989. doi:10.1161/hc4801.100038.
- Miura, T; Tanno, M; Sato, T (2010). "Mitochondrial kinase signalling pathways in myocardial protection from ischaemia/reperfusion-induced necrosis". Cardiovasc Res. 88: 7–15. doi:10.1093/cvr/cvq206.
- Halestrap, AP; Clarke, SJ; Khaliulin, I (2007). "The role of mitochondria in protection of the heart by preconditioning". Biochim Biophys Acta. 1767: 1007–1031. doi:10.1016/j.bbabio.2007.05.008.
- 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" Am J Physiol Heart Circ Physiol 2007;293:H1400–H1407.
- Gschwendt, M; Müller, HJ; Kielbassa, K; Zang, R; Kittstein, W; Rincke, G; Marks, F (Feb 1994). "Rottlerin, a novel protein kinase inhibitor". Biochem Biophys Res Commun. 199 (1): 93–8. doi:10.1006/bbrc.1994.1199.
- Davies, SP; Reddy, H; Caivano, M; Cohen, P (2001). "Specificity and mechanism of action of some commonly used protein kinase inhibitors". Biochem. J. 351: 95–105. doi:10.1042/0264-6021:3510095.
- Soltoff, SP (2001). "Rottlerin is a mitochondrial uncoupler that decreases cellular ATP levels and indirectly blocks protein kinase Cd tyrosine phosphorylation". J. Biol. Chem. 276: 37986–37992. doi:10.1074/jbc.M105073200. PMID 11498535.
- Tapia, JA; Jensen, RT; Garcia-Marin, LJ (Jan 2006). "Rottlerin inhibits stimulated enzymatic secretion and several intracellular signaling transduction pathways in pancreatic acinar cells by a non-PKC-delta-dependent mechanism". Biochim. Biophys. Acta. 1763 (1): 25–38. doi:10.1016/j.bbamcr.2005.10.007. PMID 16364465.
- Rao, VS; Seshadri, TR (1947). "Kamala dye as an anthelmintic". Proceedings of the Indian Academy of Sciences. 26 (3): 178–181.
- Mitra, R; Kapoor, LD (1976). "Kamala—the national flower of India—its ancient history and uses in Indian medicine". Indian Journal of History of Science. 11 (2): 125–132.