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1.  Sustained inhibition of PKCα reduces intravasation and lung seeding during mammary tumor metastasis in an in vivo mouse model 
Oncogene  2010;30(3):323-333.
Metastasis is the major reason for breast cancer-related deaths. Although there is a host of indirect evidence for a role of PKCα in primary breast cancer growth, its role in the molecular pathways leading to metastasis have not been comprehensively studied. By treating mice with αV5-3, a novel peptide inhibitor selective for PKCα, we were able to determine how PKCα regulates metastasis of mammary cancer cells using a syngeneic and orthotopic model. The primary tumor growth was not affected by αV5-3 treatment. However, the mortality rate was reduced and metastasis in the lung decreased by more than 90% in the αV5-3-treated mice relative to the control-treated mice. αV5-3 treatment reduced intravasation by reducing MMP-9 activities. αV5-3 treatment also reduced lung seeding of tumor cells and decreased cell migration, effects that were accompanied by a reduction in NFκB-activity and cell surface levels of the CXCL12 receptor, CXCR4. αV5-3 treatment caused no apparent toxicity in non-tumor bearing naïve mice. Rather, inhibiting PKCα protected against liver damage and increased the number of immune cells in tumor-bearing mice. Importantly, αV5-3 showed superior efficacy relative to anti-CXCR4 antibody in reducing metastasis, in vivo. Together, these data show that pharmacological inhibition of PKCα effectively reduces mammary cancer metastasis by targeting intravasation and lung seeding steps in the metastatic process and suggest that PKCα-specific inhibitors, such as αV5-3, can be used to study the mechanistic roles of PKCα specifically and may provide a safe and effective treatment for the prevention of lung metastasis of breast cancer patients.
doi:10.1038/onc.2010.415
PMCID: PMC3767436  PMID: 20856202
bioluminescence; mammary cancer; metastasis and protein kinase C
2.  PKCδ activation mediates angiogenesis via NADPH oxidase activity in PC-3 prostate cancer cells 
The Prostate  2010;71(9):946-954.
Background
PKCδ is generally known as a pro-apoptotic and anti-proliferative enzyme in human prostate cancer cells.
Methods
Here, we investigated the role of PKCδ on the growth of PC-3 human prostate cancer cells in vivo and in vitro.
Results
We found that sustained treatment with a specific PKCδ activator (ψδ receptor for active C kinase, ψδRACK) increased growth of PC-3 xenografts. There was increased levels of HIF-1α, vascular endothelial growth factor and CD31-positive cells in PC-3 xenografts, representative of increased tumor angiogenesis. Mechanistically, PKCδ activation increased the levels of reactive oxygen species (ROS) by binding to and phosphorylating NADPH oxidase, which induced its activity. Also, PKCδ-induced activation of NADPH oxidase increased the level of HIF-1α.
Conclusions
Our results using tumors from the PC-3 xenograft model suggest that PKCδ activation increases angiogenic activity in androgen-independent PC-3 prostate cancer cells by increasing NADPH oxidase activity and HIF-1α levels and thus may partly be responsible for increased angiogenesis in advanced prostate cancer.
doi:10.1002/pros.21310
PMCID: PMC3544470  PMID: 21541971
angiogenesis; HIF-1α; NADPH oxidase; prostate cancer; protein kinase C
3.  THERAPEUTIC POTENTIAL FOR PROTEIN KINASE C INHIBITOR IN VASCULAR RESTENOSIS 
Vascular restenosis, an overreaction of biological response to injury, is initialized by thrombosis and inflammation. This response is characterized by increased smooth muscle cell migration and proliferation. Available pharmacological treatments include anticoagulants, antiplatelet agents, immunosuppressants and antiproliferation agents. Protein kinase C (PKC), a large family of serine/threonine kinases, has been shown to participate in various pathological stages of restenosis. Consequently, PKC inhibitors are expected to exert a wide range of pharmacological activities therapeutically beneficial for restenosis. In this review, the roles of PKC isozymes in platelets, leukocytes, endothelial cells and smooth muscle cells are discussed, with emphasis given to smooth muscle cells. We will describe cellular and animal studies assessing prevention of restenosis with PKC inhibitors, particularly targeting -alpha, -beta, -delta and -zeta isozymes. The delivery strategy, efficacy and safety of such PKC regulators will also be discussed.
doi:10.1177/1074248410382106
PMCID: PMC3527091  PMID: 21183728
protein kinase C; smooth muscle cell; migration; proliferation; vascular restenosis
4.  βIIPKC and εPKC isozymes as potential pharmacological targets in cardiac hypertrophy and heart failure 
Cardiac hypertrophy is a complex adaptive response to mechanical and neurohumoral stimuli and under continual stressor, it contributes to maladaptive responses, heart failure and death. Protein kinase C (PKC) and several other kinases play a role in the maladaptative cardiac responses, including cardiomyocyte hypertrophy, myocardial fibrosis and inflammation. Identifying specific therapies that regulate these kinases is a major focus of current research. PKC, a family of serine/threonine kinases, has emerged as potential mediators of hypertrophic stimuli associated with neurohumoral hyperactivity in heart failure. In this review, we describe the role of PKC isozymes that are involved in cardiac hypertrophy and heart failure.
doi:10.1016/j.yjmcc.2010.10.020
PMCID: PMC3135714  PMID: 21035454
PKC signaling pathways; cardiac remodeling; heart failure
5.  Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells 
Circulation  2010;122(8):771-781.
Background
Renin released by ischemia/reperfusion (I/R) from cardiac mast cells activates a local renin-angiotensin system (RAS). This exacerbates norepinephrine release and reperfusion arrhythmias (VT/VF), making RAS a new therapeutic target in myocardial ischemia.
Methods and Results
We investigated whether ischemic preconditioning (IPC) prevents cardiac RAS activation in guinea-pig hearts ex-vivo. When I/R (20-min ischemia/30-min reperfusion) was preceded by IPC (2×5-min I/R cycles), renin and norepinephrine release and VT/VF duration were markedly decreased, a cardioprotective anti-RAS effect. Activation and blockade of adenosine A2b/A3-receptors, and activation and inhibition of PKCε, mimicked and prevented, respectively, the anti-RAS effects of IPC. Moreover, activation of A2b/A3-receptors, or activation of PKCε, prevented degranulation and renin release elicited by peroxide in cultured mast cells (HMC-1). Activation and inhibition of mitochondrial aldehyde dehydrogenase type-2 (ALDH2) also mimicked and prevented, respectively, the cardioprotective anti-RAS effects of IPC. Furthermore, ALDH2 activation inhibited degranulation and renin release by reactive aldehydes in HMC-1. Notably, PKCε and ALDH2 were both activated by A2b/A3-receptor stimulation in HMC-1, and PKCε inhibition prevented ALDH2 activation.
Conclusions
The results uncover a signaling cascade initiated by A2b/A3-receptors, which triggers PKCε-mediated ALDH2 activation in cardiac mast cells, contributing to IPC-induced cardioprotection by preventing mast-cell renin release and the dysfunctional consequences of local RAS activation. Thus, unlike classical IPC where cardiac myocytes are the main target, cardiac mast cells are the critical site at which the cardioprotective anti-RAS effects of IPC develop.
doi:10.1161/CIRCULATIONAHA.110.952481
PMCID: PMC2927811  PMID: 20697027
Renin; Ischemia; Reperfusion; Norepinephrine; Arrhythmia
6.  Highly Specific Modulators of Protein Kinase C Localization: Applications to Heart Failure 
Heart failure (HF) in which the blood supply does not match the body's needs, affects 10% of the population over 65 years old. The protein kinase C (PKC) family of kinases has a key role in normal and disease states. Here we discuss the role of PKC in HF and focus on the use of specific PKC regulators to identify the mechanism leading to this Pathology and potential leads for therapeutics.
doi:10.1016/j.ddmec.2010.07.001
PMCID: PMC2998291  PMID: 21151743
7.  Regulation of mitochondrial processes: a target for heart failure 
Cardiac mitochondria, the main source of energy as well as free radicals, are vital organelles for normal functioning of the heart. Mitochondrial number, structure, turnover and function are regulated by processes such as mitochondrial protein quality control, mitochondrial fusion and fission and mitophagy. Recent studies suggest that abnormal changes in these mitochondrial regulatory processes may contribute to the pathology of heart failure (HF). Here we discuss these processes and their potential as therapeutic targets.
doi:10.1016/j.ddmec.2010.07.002
PMCID: PMC3026286  PMID: 21278905
8.  Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant 
In approximately one billion people, a point mutation inactivates a key detoxifying enzyme, aldehyde dehydrogenase (ALDH2). This mitochondrial enzyme metabolizes toxic biogenic and environmental aldehydes, including the endogenously produced 4-hydroxynonenal (4HNE) and the environmental pollutant, acrolein. ALDH2 also bioactivates nitroglycerin, but it is best known for its role in ethanol metabolism. The accumulation of acetaldehyde following the consumption of even a single alcoholic beverage leads to the Asian Alcohol-induced Flushing Syndrome in ALDH2*2 homozygotes. The ALDH2*2 allele is semi-dominant and heterozygotic individuals exhibit a similar, but not as severe phenotype. We recently identified a small molecule, Alda-1, which activates wild-type ALDH2 and restores near wild-type activity to ALDH2*2. The structures of Alda-1 bound to ALDH2 and ALDH2*2 reveal how Alda-1 activates the wild-type enzyme and how it restores the activity of ALDH2*2 by acting as a structural chaperone.
doi:10.1038/nsmb.1737
PMCID: PMC2857674  PMID: 20062057
9.  Mitochondrial import of PKCε is mediated by HSP90: a role in cardioprotection from ischaemia and reperfusion injury 
Cardiovascular Research  2010;88(1):83-92.
Aims
Protein kinase C epsilon (PKCε) is critical for cardiac protection from ischaemia and reperfusion (IR) injury. PKCε substrates that mediate cytoprotection reside in the mitochondria. However, the mechanism enabling mitochondrial translocation and import of PKCε to enable phosphorylation of these substrates is not known. Heat shock protein 90 (HSP90) is a cytoprotective protein chaperone that participates in mitochondrial import of a number of proteins. Here, we investigated the role of HSP90 in mitochondrial import of PKCε.
Methods and results
Using an ex vivo perfused rat heart model of IR, we found that PKCε translocates from the cytosol to the mitochondrial fraction following IR. Immunogold electron microscopy and mitochondrial fractionation demonstrated that following IR, mitochondrial PKCε is localized within the mitochondria, on the inner mitochondrial membrane. Pharmacological inhibition of HSP90 prevented IR-induced interaction between PKCε and the translocase of the outer membrane (Tom20), reduced mitochondrial import of PKCε, and increased necrotic cell death by ∼70%. Using a rational approach, we designed a 7-amino acid peptide activator of PKCε, derived from an HSP90 homologous sequence located in the C2 domain of PKCε (termed ψεHSP90). Treatment with this peptide (conjugated to the cell permeating TAT protein-derived peptide, TAT47–57) increased PKCε–HSP90 protein–protein interaction, enhanced mitochondrial translocation of PKCε, increased phosphorylation and activity of an intra-mitochondrial PKCε substrate, aldehyde dehydrogenase 2, and reduced cardiac injury in ex vivo and in vivo models of myocardial infarction.
Conclusion
Our results suggest that HSP90-mediated mitochondrial import of PKCε plays an important role in the protection of the myocardium from IR injury.
doi:10.1093/cvr/cvq154
PMCID: PMC2936125  PMID: 20558438
Protein kinase C epsilon; Mitochondria; Protein–protein interaction; Ischaemia reperfusion; Heat shock protein 90
10.  Mitochondrial aldehyde dehydrogenase and cardiac diseases 
Cardiovascular Research  2010;88(1):51-57.
Numerous conditions promote oxidative stress, leading to the build-up of reactive aldehydes that cause cell damage and contribute to cardiac diseases. Aldehyde dehydrogenases (ALDHs) are important enzymes that eliminate toxic aldehydes by catalysing their oxidation to non-reactive acids. The review will discuss evidence indicating a role for a specific ALDH enzyme, the mitochondrial ALDH2, in combating oxidative stress by reducing the cellular ‘aldehydic load’. Epidemiological studies in humans carrying an inactive ALDH2, genetic models in mice with altered ALDH2 levels, and small molecule activators of ALDH2 all highlight the role of ALDH2 in cardioprotection and suggest a promising new direction in cardiovascular research and the development of new treatments for cardiovascular diseases.
doi:10.1093/cvr/cvq192
PMCID: PMC2936126  PMID: 20558439
ALDH2; Mitochondria; Ischaemia; Nitroglycerin; Alda-1
11.  Focus On: The Cardiovascular System 
Alcohol Research & Health  2010;33(1-2):76-86.
Although heavy alcohol consumption has deleterious effects on heart health, moderate drinking is thought to have cardioprotective effects, reducing the risk of coronary artery disease and improving prognosis after a myocardial infarction. It still is unclear, however, if this effect can be achieved with all types of alcoholic beverages and results from the alcohol itself, from other compounds found in alcoholic beverages, or both. For example, the polyphenolic compound resveratrol, which is found particularly in red wine, can reduce the risk of atherosclerosis; however, it is not clear if the resveratrol levels present in wine are sufficient to achieve this result. Alcohol itself contributes to cardioprotection through several mechanisms. For example, it can improve the cholesterol profile, increasing the levels of “good” cholesterol and reducing the levels of “bad” cholesterol. Alcohol also may contribute to blood clot dissolution and may induce a phenomenon called pre-conditioning, whereby exposure to moderate alcohol levels (like short bouts of blood supply disruption [i.e., ischemia]), and result in reduced damage to the heart tissue after subsequent prolonged ischemia. Finally, the enzyme aldehyde dehydrogenase (ALDH) 2, which is involved in alcohol metabolism, also may contribute to alcohol-related cardioprotection by metabolizing other harmful aldehydes that could damage the heart muscle.
PMCID: PMC3887499  PMID: 23579938
Alcohol consumption; light drinking; moderate drinking; effects and consequences of alcohol and other drug use; beneficial moderate alcohol consumption; risk and protective factors; risk-benefit; cardiovascular system; cardioprotection; wine; red wine; French Paradox; cholesterol; resveratrol; aldehyde dehydrogenase 2

Results 1-11 (11)