8. Bowman JC, Steinberg SF, Jiang T, Geenen DL, Fishman GI, et al. (1997) Expression of protein kinase C beta in the heart causes hypertrophy in adult mice and sudden death in neonates. J Clin Invest 100: 2189–2195. 9. Ferreira JC, Koyanagi T, Palaniyandi SS, Fajardo G, Churchill EN, et al. (2011) Pharmacological inhibition of betaIIPKC is cardioprotective in late-stage hypertrophy. J Mol Cell Cardiol 51: 980–987. 10. Ferreira JCB, Brum PC, Mochly-Rosen D (2011) betaIIPKC and epsilonPKC isozymes as potential pharmacological targets in cardiac hypertrophy and heart failure. J Mol Cell Cardiol 51: 479–484. 11. Palaniyandi SS, Ferreira JCB, Brum PC, Mochly-Rosen D (2011) PKCbetaII inhibition attenuates myocardial infarction induced heart failure and is associated with a reduction of fibrosis and pro-inflammatory responses. J Cell Mol Med 15: 1769–1777. 12. Ferreira JC, Moreira JB, Campos JC, Pereira MG, Mattos KC, et al. (2011) Angiotensin receptor blockade improves the net balance of cardiac Ca(2+) handling-related proteins in sympathetic hyperactivity-induced heart failure. Life Sci 88: 578–585. 13. Inagaki K, Iwanaga Y, Sarai N, Onozawa Y, Takenaka H, et al. (2002) Tissue angiotensin II during progression or ventricular hypertrophy to heart failure in hypertensive rats; differential effects on PKC epsilon and PKC beta. J Mol Cell Cardiol 34: 1377–1385. 14. Souroujon MC, Mochly-Rosen D (1998) Peptide modulators of protein-protein interactions in intracellular signaling. Nat Biotechnol 16: 919–924. 15. Simonis G, Briem SK, Schoen SP, Bock M, Marquetant R, et al. (2007) Protein kinase C in the human heart: differential regulation of the isoforms in aortic stenosis or dilated cardiomyopathy. Mol Cell Biochem 305: 103–111. 16. Stebbins EG, Mochly-Rosen D (2001) Binding specificity for RACK1 resides in the V5 region of beta II protein kinase C. J Biol Chem 276: 29644–29650. 17. Kim J, Choi YL, Vallentin A, Hunrichs BS, Hellerstein MK, et al. (2008) Centrosomal PKCbetaII and pericentrin are critical for human prostate cancer growth and angiogenesis. Cancer Res 68: 6831–6839. 18. Inagaki K, Chen L, Ikeno F, Lee FH, Imahashi K, et al. (2003) Inhibition of delta-protein kinase C protects against reperfusion injury of the ischemic heart in vivo. Circulation 108: 2304–2307. 19. Johnson JA, Mochly-Rosen D (1995) Inhibition of the spontaneous rate of contraction of neonatal cardiac myocytes by protein kinase C isozymes. A putative role for the epsilon isozyme. Circ Res 76: 654–663. 20. Iwanaga Y, Kihara Y, Hasegawa K, Inagaki K, Yoneda T, et al. (1998) Cardiac endothelin-1 plays a critical role in the functional deterioration of left ventricles during the transition from compensatory hypertrophy to congestive heart failure in salt-sensitive hypertensive rats. Circulation 98: 2065–2073. 21. Paulus WJ, van Ballegoij JJ (2010) Treatment of heart failure with normal ejection fraction: an inconvenient truth! J Am Coll Cardiol 55: 526–537. 22. Wakasaki H, Koya D, Schoen FJ, Jirousek MR, Ways DK, et al. (1997) Targeted overexpression of protein kinase C beta2 isoform in myocardium causes cardiomyopathy. Proc Natl Acad Sci U S A 94: 9320–9325. 23. Bowling N, Walsh RA, Song G, Estridge T, Sandusky GE, et al. (1999) Increased protein kinase C activity and expression of Ca2+-sensitive isoforms in the failing human heart. Circulation 99: 384–391. 24. Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin- proteasome system by protein aggregation. Science 292: 1552–1555. 25. Sohn D, Totzke G, Schulze-Osthoff K, Janicke RU (2006) Friend or foe? The proteasome in combined cancer therapy. Cell Cycle 5: 841–845. 26. Churchill EN, Ferreira JC, Brum PC, Szweda LI, Mochly-Rosen D (2010) Ischaemic preconditioning improves proteasomal activity and increases the degradation of deltaPKC during reperfusion. Cardiovasc Res 85: 385–394. 27. Palaniyandi SS, Sun L, Ferreira JC, Mochly-Rosen D (2009) Protein kinase C in heart failure: a therapeutic target? Cardiovasc Res 82: 229–239. PKCbII Inhibition in Heart Failure 28. Lu H, Zong C, Wang Y, Young GW, Deng N, et al. (2008) Revealing the dynamics of the 20 S proteasome phosphoproteome: a combined CID and electron transfer dissociation approach. Mol Cell Proteomics 7: 2073–2089. 29. Asai M, Tsukamoto O, Minamino T, Asanuma H, Fujita M, et al. (2009) PKA rapidly enhances proteasome assembly and activity in in vivo canine hearts. J Mol Cell Cardiol 46: 452–462. 30. Zong C, Gomes AV, Drews O, Li X, Young GW, et al. (2006) Regulation of murine cardiac 20S proteasomes: role of associating partners. Circ Res 99: 372–380. 31. Gomes AV, Young GW, Wang Y, Zong C, Eghbali M, et al. (2009) Contrasting proteome biology and functional heterogeneity of the 20 S proteasome complexes in mammalian tissues. Mol Cell Proteomics 8: 302–315. 32. Willis MS, Schisler JC, Portbury AL, Patterson C (2009) Build it up-Tear it down: protein quality control in the cardiac sarcomere. Cardiovasc Res 81: 439–448. 33. Hedhli N, Lizano P, Hong C, Fritzky LF, Dhar SK, et al. (2008) Proteasome inhibition decreases cardiac remodeling after initiation of pressure overload. Am J Physiol Heart Circ Physiol 295: H1385–1393. 34. Meiners S, Dreger H, Fechner M, Bieler S, Rother W, et al. (2008) Suppression of cardiomyocyte hypertrophy by inhibition of the ubiquitin-proteasome system. Hypertension 51: 302–308. 35. Farout L, Mary J, Vinh J, Szweda LI, Friguet B (2006) Inactivation of the proteasome by 4-hydroxy-2-nonenal is site specific and dependant on 20S proteasome subtypes. Arch Biochem Biophys 453: 135–142. 36. Nowis D, Maczewski M, Mackiewicz U, Kujawa M, Ratajska A, et al. (2010) Cardiotoxicity of the anticancer therapeutic agent bortezomib. Am J Pathol 176: 2658–2668. 37. Chen Q, Liu JB, Horak KM, Zheng H, Kumarapeli AR, et al. (2005) Intrasarcoplasmic amyloidosis impairs proteolytic function of proteasomes in cardiomyocytes by compromising substrate uptake. Circ Res 97: 1018–1026. 38. Su H, Wang X (2010) The ubiquitin-proteasome system in cardiac proteino- pathy: a quality control perspective. Cardiovasc Res 85: 253–262. 39. Orciuolo E, Buda G, Cecconi N, Galimberti S, Versari D, et al. (2007) Unexpected cardiotoxicity in haematological bortezomib treated patients. British Journal of Haematology 138: 396–403. 40. Bulteau AL, Szweda LI, Friguet B (2002) Age-dependent declines in proteasome activity in the heart. Arch Biochem Biophys 397: 298–304. 41. Johns TN, Olson BJ (1954) Experimental myocardial infarction. I. A method of coronary occlusion in small animals. Ann Surg 140: 675–682. 42. Hemeryck A, Geerts R, Monbaliu J, Hassler S, Verhaeghe T, et al. (2007) Tissue distribution and depletion kinetics of bortezomib and bortezomib-related radioactivity in male rats after single and repeated intravenous injection of 14 C-bortezomib. Cancer Chemother Pharmacol 60: 777–787. 43. Vallentin A, Mochly-Rosen D (2007) RBCK1, a protein kinase CbetaI (PKCbetaI)-interacting protein, regulates PKCbeta-dependent function. J Biol Chem 282: 1650–1657. 44. Disatnik MH, Boutet SC, Lee CH, Mochly-Rosen D, Rando TA (2002) Sequential activation of individual PKC isozymes in integrin-mediated muscle cell spreading: a role for MARCKS in an integrin signaling pathway. J Cell Sci 115: 2151–2163. 45. Antony JM, van Marle G, Opii W, Butterfield DA, Mallet F, et al. (2004) Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination. Nat Neurosci 7: 1088–1095. 46. Gray MO, Karliner JS, Mochly-Rosen D (1997) A selective epsilon-protein kinase C antagonist inhibits protection of cardiac myocytes from hypoxia- induced cell death. J Biol Chem 272: 30945–30951. PLoS ONE | www.plosone.org 11 March 2012 | Volume 7 | Issue 3 | e33175