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Figure 5-1: Relative roles of cardiomyocyte hypertrophy, hyperplasia, and apoptosis in physiologic and pathologic cardiac hypertrophy, along with the functional differences between compensated hypertrophy and heart failure.

Figure 5-2: A schema for signal-transduction pathways that activate transcriptional regulation and induce hypertrophic genes. G protein-coupled receptor agonists binding to their receptors activate phospholipase C (PLC) f^ via the dissociated G( subunit of a GTP-binding protein of the Gq class (GqO(). PLCf-'] catalyzes the hydrolysis of phosphatidyl-inositol bisphosphate (PIP2) into diacylglycerol (DAG), which activates protein kinase C PKC and inositol trisphosphate (IP3), which stimulates calcium release from intracellular stores. PKC activated by DAG and ± calcium initiates cascades of phosphorylation. One of the downstream targets of PKC is the ras-raf mitogen-activated protein kinase (MAPK) cascade. Insulin-like growth factor (IGF)-1, basic fibroblast growth factor (bFGF), or epidermal growth factor (EGF) interacts with cognate membrane tyrosine kinase receptors, which activate ras by the growth factor receptor-bound protein. Ras activates raf, MAPK/ERK-activating kinase (MEK), and extracellular signal regulated kinase (ERK). Cellular stresses activate other members of the MAPK family, c-Jun N-terminal kinase (JNK) and p38-MAPK, but precise signaling elements are not as well defined as in the ERK cascade. The MAPK kinase (MKK) and small G proteins are likely to be involved. Ras, either directly or indirectly, may activate JNK and p38-MAPK. Signaling through interleukin-1 (IL-1) and cardiotrophin-1 (CT-1) receptors involves gp130, which acts as a signal-transducing receptor component. The binding of ligands to their cognate receptors results in receptor dimerization, autophosphorylation, and activation of the associated Janus kinase (JAK). In turn, JAK activates members of the STAT (signal transducer and activator of transcription) family. PKC activation increases calcium concentration through phosphorylation of L-type calcium channel and IP3 mediated calcium release from intracellular stores. This leads to stimulation of the calcium-dependent phosphatase calcineurin. Activated calcineurin dephosphorylates nuclear factor of activated T lymphocytes (NFAT), which translocates into the nucleus to interact with multiple transcription factors.

Figure 5-3: Schematic diagram of cardiomyocyte signaling pathways that regulate calcium levels and excitation-contraction coupling. Calcium enters into the cytosol via the voltage-sensitive L-type channel. Calcium then interacts with the ryanodine receptor, which triggers augmented calcium release from the sarcoplasmic reticulum (SR). Calcium is bound to troponin (Tn) C, which activates actin myosin cross-bridge development and shortening. Hydrolysis of ATP to ADP mediated by the ATPase at the head of myosin molecules in the thick filament provides energy for the process. Tn I inhibits cross-bridge formation when calcium is not bound to Tn C. Tn T anchors the Tn complex to the thin filament actin. Calcium is then released and resequestered into the SR by an ATPase where it is bound to the SR storage proteins calsequestrin and calreticulum. Phospholamban in its dephosphorylated state inhibits SR ATPase activity and phosphorylation relieves this inhibition. Binding of agonist to the ^-adrenergic receptor activates adenylate cyclase via dissociation of the Gsd subunit. Adenylate cyclase generates cyclic AMP from ATP, which, in turn, activates cyclic AMP-dependent protein kinase A (PKA). PKA regulates myocardial contractility by phosphorylation of the L-type calcium channel, leading to increased calcium entry, by phosphorylating phospholamban and resultant enhanced SR ATPase activity, and by phosphorylating regulatory proteins of the myofilament leading to decreased calcium sensitivity. The net enhancement of intracellular calcium concentration is restored by the coordinated activity of the Na+-H+ and Na+-Ca2+ exchangers (Ex).

' Figure 5-4: Schematic diagram of the mechanisms responsible for the development of the anatomic and functional cardiac phenotypes in physiologic and pathologic hypertrophy. Abnormalities at one or multiple levels in this putative closed-loop system may be responsible for the transition between compensated and decompensated hypertrophy.

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