p38 and c-jun N-terminal and mitogen-activated protein kinases

Mitogen-activated protein kinases (MAPK) are important components of signaling modules activated by neurotransmitters, cytokines, and growth factors, as well as chemical and mechanical stressors. p38 MAPK is one of these kinases that has diverse cellular function including mitogenic activity, control of glucose metabolism, and activation of apoptotic pathways. The c-Jun N-terminal kinase (JNK) branch of the MAPK signaling pathway also regulates cellular differentiation, stress responsiveness and apoptosis in multicellular eukaryotic organisms.

Paraphenylpentadecanoic acid (pPPA)

Paraphenylpentadecanoic acid (pPPA) is a fatty acid analog that can be radiolabeled (eg. with ¹²³I) and used as an imaging agent to assess fatty acid uptake into tissues. It is often used to determine whether fatty acid uptake is altered in the hearts of patients. This is established by using a gamma-camera to determine the amount of radiolabeled pPPA taken up by the heart.

Perhexilene

Perhexilene is a compound that has found some use in the treatment of angina pectoris (particularly in Australia). Its exact mechanism of action is unknown, although it has been suggested to inhibit fatty acid uptake into heart mitochondria by inhibiting an enzyme called carnitine palmitoyltransferase-1.

Peroxides

Peroxides are chemical substances that contain a peroxo unit - one that has an oxygen-oxygen bond (O–O) and the chemical formula of O₂^2-. The most familiar example of a peroxide is hydrogen peroxide.

Peroxiredoxin III

Peroxiredoxin III is specifically localized to mitochondria and is believed to play an important role in the regulation of cellular redox status by serving as a primary line of defense against H₂O₂ produced during respiration.

Peroxisome proliferator-activated receptor alpha (MHC-PPARα)

Peroxisome proliferator-activated receptor (PPARα) is a nuclear receptor involved in transcriptional regulation of proteins. PPA0052α has many functions, including regulating enzymes involved in the control of fatty acid oxidation in the heart. MHC-PPARα refers to an experimental approach that is used to selectively express Peroxisome proliferator-activated receptor alpha in muscle. This is achieved by linking the Peroxisome proliferator-activated receptor a gene to the myosin heavy chain (MHC) promoter. The production of transgenic mice from embryonic stem cells that contain the MHC-PPARα gene will result in mice that overexpress PPARa targeted to muscle.

Peroxisome proliferator-activated receptorg (PPARγ)

Peroxisomal proliferators-activated receptors are nuclear receptors involved in the transcriptional regulation of proteins. One of these nuclear receptors is PPARγ, which modifies the expression of a number of proteins, including those involved in insulin sensitivity and lipid metabolism. Activation of PPARγ is a therapeutic approach to treating diabetes, which may in part be due lowering blood fatty acid levels, secondary to decreasing fatty acid release from adipose tissue.

Peroxisome proliferator-activated receptor a (PPARα)

PPARα is a nuclear receptor involved in the transcriptional regulation of proteins. PPARa has many functions, including regulating the expression of many enzymes involved in the control of fatty acid oxidation in muscle.

Peroxynitrite (ONOO^–)

Peroxynitrite (ONOO^–) is formed by the combination of NO with O₂–. ONOO– then rapidly decomposes to form highly creative oxidant species.

Phosphatidylinositol (4,5) biphosphate (PtdIns(4,5)-P2)

Phosphoinositol-4,5-bisphosphate (PIP2) is an intracellular signalling molecule produced by phosphoinositol-4-phosphate- 5-kinase. PIP2 is produced by various stimuli, including activation of the insulin receptor. PIP2 then acts as a substrate for phosphoinositol 3-kinase (PI 3-K) to produce PtdIns(3,4,5)-P3 (see below).

Phosphatidylinositol 3-kinase

Phosphatidylinositol 3-kinase is an intracellular kinase activated by lipids that phosphorylates the cellular phospholipid, phosphatidylinositol. The product of this reaction is involved in many intracellular signaling pathways, including the control of energy metabolism.

Phosphodiesterase type 5 (PDE5)

Phosphodiesterases are enzymes that cleave cyclic nucleotides such as cAMP and cGMP. PDE5 is a phosphodiesterase isoform that cleaves cGMP. Inhibition of PDE5 results in smooth muscle relaxation, and is the target for sildenafil (Viagra). This explains the coronary vasodilatory effect of sildenafil, as well as the effects on penial erection.

Phosphodiesterase type-5 (PDE5) inhibitors

PDE-5 is the enzyme that metabolises cyclic guanosine monophosphate (cGMP). Therefore, PDE-5 inhibitors will prevent the degradation of cGMP and increase tissue levels of cGMP. A well known example of a PDE-5 inhibitor is sildenafil (marketed as Viagra®). In addition to its smooth muscle relaxing effects in the penis, sildenafil can also induce pulmonary and coronary vasodilation, precondition the myocardium, reduce platelet activation, and potentially reduce early graft occlusion. As a result, PDE-5 inhibitors have potential in the treatment of both pulmonary hypertension and ischemic heart disease.

Phosphofructokinase

Phosphofructokinase (PFK) is the rate-limiting enzyme involved in the glycolytic pathway. It is a highly regulated enzyme that converts fructose 6-phosphate to fructose 1,6 bisphosphate. Activation of PFK results in an activation of glycolysis, while inhibition of PFK results in an inhibition of glycolysis.

Phosphoinositide-dependent protein kinase-1 (PDK-1) and PKB (protein kinase B also known as Akt)

3-phosphinositide-dependent kinase-1 (PDK-1) is a signaling kinase activated by PtdIns(3,4,5)-P₃. This kinase then acts on downstream kinases such as PKB and protein kinase C to mediate numerous cellular events. Protein kinase B is an intracellular kinase that is important in regulating glucose metabolism. It is a kinase downstream of PDK-1, and insulin activation of PKB will result in GLUT-4 translocation to the cell membrane, thereby stimulating glucose uptake.

Phosphoribosylpyrophosphate

Phosphoribosylpyrophosphate is an intermediate in the purine biosynthesis pathway. Purines are an important component of DNA and RNA.

Phosphorylation

Phosphorylation refers to the process of adding a phosphate group to proteins, usually a tyrosine, serine or threonine residue. This occurs via the action of numerous kinases. Phosphorylation is a very important mechanism that regulates enzyme activity, and is a component of most cellular signaling pathways.

Plasminogen activator inhibitor (PAI)-1

Plasminogen activator inhibitor (PAI)-1 is a protein that inhibits fibrinolysis and proteolysis. Increases in PAI-1 levels have been associated with increased risk of myocardial infarction and decreased risk of cerebrovascular events.

Pleckstrin homology domain

Pleckstrin homology (PH) domains are the 11th most common domain in the human genome, and are best known as domains in an enzyme that have the ability to target cellular membranes by binding specifically to phosphoinositides. Most PH domains are not capable of independent membrane targeting and usually require both phosphoinositide and non-phosphoinositide determinants for their subcellular localization.

PRKAG2

PRKAG2 is the gene that encodes the g2 subunit of AMPactivated protein kinase (AMPK). Mutations in PRKAG2 have recently been shown to cause cardiac hypertrophy, cardiac glycogen accumulation, Wolff-Parkinson-White syndrome, and conduction system disease causing pre-excitation.

Proanthocyanidins

Proanthocyanidins are components of grape seeds and are the main phenolic antioxidant of red wine. They are thought to have beneficial antioxidant effects.

Prostacyclin

Prostacyclin is a prostaglandin that has a number of important biological effects, one of which is a potent vasodilatory action in blood vessels.

Prostaglandins, thromboxanes and leukotrienes

Prostaglandins, thromboxanes and leukotrienes are derivatives of arachidonic acid, and belong to a class of biologically active lipids called eicosanoids. They have diverse effects in the body, including vasodilation, vasconstriction, clot formation and mediators of inflammation.

Protein carbonyls

Free radicals can target lipids, DNA or proteins. One of the products of free radical damage to proteins is the formation of protein carbonyls. Oxidatively modified forms of proteins accumulate during oxidativestress.

Protein kinase B (PKB)

Protein kinase B (PKB) is an intracellular kinase that is important in regulating glucose metabolism. It is a kinase downstream of PI3K, and insulin activation of PKB will result in GLUT4 translocation to the cell membrane, thereby stimulating glucose uptake.

Protein kinase C (PKC)

Protein kinase C (PKC) is an important kinase involved in cellular signaling. It is activated by lipids (diacylglycerols) released from the phospholipids membrane. There is a considerable research interest in the role of PKC modification in the ischemic heart.

Protein kinase (AMPK) pathway

AMP-activated protein kinase (AMPK) is a widely distributed cellular kinase that is activated during times of metabolic stress. It has been termed a cellular “fuel gauge”, and primarily functions to turn off energyconsuming pathways and turn on energy-producing pathways during metabolic stress.

Proteins of the Rho-family

The Rho-family of proteins are proteins involved in cellular signalling. An example of this is Rho A, which is involved in vascular smooth muscle proliferation. Platelet-derived growth factor can increase Rho A protein. Rho kinase plays an important role in this process as an effector of Rho A. The RhoA/Rho kinase pathway can mediate calcium sensitization in vascular smooth muscle.

Protocatechuic acid

Protocatechuic acid is a naturally occurring antioxidant. It is a phenolic compound found in various plants, including grapes.

Proto-oncogene Cbl

Cb1 is a protooncogene product that was initially identified as part of a murine retrovirus transforming protein. Cb1 is ubiquitously expressed protein containing a set of sequences providing interactions with a wide range of receptor and nonreceptor tyrosine kinases and signaling proteins. These properties permit Cb1 to take part in many protein-protein interactions as an adaptor, which forms multimolecular signaling complexes, and coordinates the activity of its components.

PtdIns(3,4,5)-P₃

PtdIns(3,4,5)-P₃ is released from membrane phosphatidylinositol as part of a signaling cascade initiated by a number of different hormones, including insulin. PtdIns(3,4,5)-P₃ activates downstream targets, such as 3-phosphinositide-dependent kinase-1 (PDK-1). This kinase then acts on downstream kinases such as PKB and protein kinase C to mediate numerous cellular events.

Pyruvate

Pyruvate is an intermediate molecule in the metabolism of both glucose and lactates. Glycolysis produces two pyruvate molecules from each molecule of glucose metabolized. Lactate can also be converted to pyruvate by the enzyme lactate dehydrogenase. In the heart, much of the pyruvate produced is taken up by the mitochondria and used by pyruvate dehydrogenase to produce acetyl coenzyme A.

Pyruvate dehydrogenase (PDH)

Pyruvate dehydrogenase (PDH) is an intramitochondrial complex that converts pyruvate (which primarily originates from glucose or lactate) into acetyl CoA. PDH is the ratlimiting enzyme for the mitochondrial metabolism of carbohydrates. Maintaining mitochondrial glucose metabolism is an important therapeutic strategy to protect the ischemic heart. Therefore, activating PDH is a potential therapeutic approach to treating heart disease.

Pyruvate dehydrogenase (PDH) kinase

Pyruvate dehydrogenase (PDH) kinase is an intramitochondrial kinase that phosphorylates and inhibits PDH. Since PDH is the ratelimiting enzyme for the mitochondrial metabolism of carbohydrates, activation of PDH kinase will result in a decrease in the mitochondrial metabolism of carbohydrates. Maintaining mitochondrial glucose metabolism is an important therapeutic strategy to protect the ischemic heart. Therefore, inhibition of PDH kinase is a potential therapeutic approach to treating ischemic heart disease.

Pyruvate dehydrogenase complex (PDH)

The PDH complex is composed of a number of enzymes whose function is to convert pyruvate (which mainly originates from glycolysis or lactate dehydrogenase) and CoA into acetyl CoA. In the process, NAD+ is reduced to NADH. The acetyl CoA produced enters the tricarboxylic acid cycle where it is further metabolized, whereas NADH is used as an electron donor by the mitochondrial electron transport chain. PDH is the rate-limiting step in glucose oxidation.

Reduced nicotinamide adenine dinucleotide phosphate oxidase

Reduced nicotinamide adenine dinucleotide phosphate oxidase is an enzyme present in phagocytes such as neutrophils and macrophages. This enzyme is an important source of free radicals.

Reperfusion injury

Reperfusion injury is a term used to describe injury that can occur to the heart muscle during the period of reperfusion following ischemia. As an example, an excessive reliance of the heart on fatty acids during reperfusion or the generation of oxygenderived free radicals can cause muscle injury during reperfusion of the ischemic heart.

Resistin

Resistin is an adipose tissue-specific factor which is reported to induce insulin resistance, linking diabetes to obesity.

Ryanodine

Ryanodine is an inhibitor of the calcium channel that releases calcium from the sarcoplasmic reticulum. It was an important tool in first characterizing this channel, which is often called the ryanodine-sensitive calcium channel.