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I. Introduction II. Overview of Myocardial Substrate Metabolism A. Regulation of metabolic pathways in the heart B. Carbohydrate metabolism C. Fatty acid metabolism D. Ketone body metabolism E. Interregulation of [...]

In contrast to skeletal muscle isoforms of myosin binding protein C (MyBP-C), the cardiac isoform has 11 rather than 10 fibronectin or Ig modules (modules are identified as CO to C10, N[H.sub.2] to COOH terminus), 3 phosphorylation sites between modules C1 and C2, and 28 additional amino acids rich in proline in C5. Phosphorylation between C1 and C2 increases maximum Ca-activated force (Fmax), alters thick filament structure, and increases the probability of myosin heads on the thick filament binding to actin on the thin filament. Unphosphorylated C1C2 fragment binds to myosin, but phosphorylation inhibits the binding. MyBP-C also binds to actin. Using two types of immunoprecipitation and cosedimentation, we show that fragments of MyBP-C containing CO bind to actin. In low concentrations CO-containing fragments bind to skinned fibers when the N[H.sub.2] terminus of endogenous MyBP-C is bound to myosin, but not when MyBP-C is bound to actin. C1C2 fragments bind to skinned fibers when endogenous MyBP-C is bound to actin but not to myosin. Disruption of interactions of endogenous CO with a high concentration of added COC2 fragments produces the same effect on contractility as extraction of MyBP-C, namely decrease in Fmax and increase in Ca sensitivity. These results suggest that cardiac contractility can be regulated by shifting the binding of the N[H.sub.2] terminus of MyBP-C between actin and myosin. This mechanism may have an effect on diastolic filling of the heart. KEY WORDS: C1C2 * CO * cardiomyopathy * relaxation * phosphorylation

The transcription factor nuclear factor-[kappa]B (NF-[kappa]B) regulates expression of a variety of genes involved in immune responses, inflammation, proliferation, and programmed cell death (apoptosis). Here, we show that in rat neonatal ventricular cardiomyocytes, activation of NF-[kappa]B is involved in the hypertrophic response induced by myotrophin, a hypertrophic activator identified from spontaneously hypertensive rat heart and cardiomyopathic human hearts. Myotrophin treatment stimulated NF-[kappa]B nuclear translocation and transcriptional activity, accompanied by I[kappa]B-[alpha] phosphorylation and degradation. Consistently, myotrophin-induced NF-[kappa]B activation was enhanced by wild-type I[kappa]B kinase (IKK) [beta] and abolished by the dominant-negative IKK[beta] or a general PKC inhibitor, calphostin C. Importantly, myotrophin-induced expression of two hypertrophic genes (atrial natriuretic factor [ANF] and c-myc) and also enhanced protein synthesis were partially inhibited by a potent NF-[kappa]B inhibitor, pyrrolidine dithio-carbamate (PDTC), and calphostin C. Expression of the dominantnegative form of I[kappa]B-[alpha] or IKK[beta] also partially inhibited the transcriptional activity of ANF induced by myotrophin. These findings suggest that the PKC-IKK-NF-[kappa]B pathway may play a critical role in mediating the myotrophin-induced hypertrophic response in cardiomyocytes.

We investigated 18 AIDS hearts (5 with and 13 without cardiomyopathy) by using immunocytochemistry and computerized image analysis regarding the roles of HIV-1 proteins and tumor necrosis factor ligands in HIV cardiomyopathy (HIVCM). HIVCM and cardiomyocyte apoptosis were significantly related to each other and to the expression by inflammatory cells of gp120 and tumor necrosis factor-[alpha]. In HIVCM heart, active caspase 9, a component of the mitochondrion-controlled apoptotic pathway, and the elements of the death receptor-mediated pathway, tumor necrosis factor-[alpha] and Fas ligand, were expressed strongly on macrophages and weakly on cardiomyocytes. HIVCM showed significantly greater macrophage infiltration and cardiomyocyte apoptosis rate compared with non-HIVCM. HIV-1 entered cultured neonatal rat ventricular myocytes by macropinocytosis but did not replicate. HIV-1- or gp120-induced apoptosis of rat myocytes through a mitochondrion-controlled pathway, which was inhibited by heparin, AOPRANTES, or pertussis toxin, suggesting that cardiomyocyte apoptosis is induced by signaling through chemokine receptors. In conclusion, in patients with HIVCM, cardiomyocytes die through both mitochondrion- and death receptor-controlled apoptotic pathways.

The transthyretin (TTR) amyloid diseases are of keen interest, because there are >80 mutations that cause, and a few mutations that suppress, disease. The V122I variant is the most common amyloidogenic mutation worldwide, producing familial amyloidotic cardiomyopathy primarily in individuals of African descent. The substitution shifts the tetramer-folded monomer equilibrium toward monomer (lowers tetramer stability) and lowers the kinetic barrier associated with rate-limiting tetramer dissociation (pH 7; relative to wild-type TTR) required for amyloid fibril formation. Fibril formation is also accelerated because the folded monomer resulting from the tetramer-folded monomer equilibrium rapidly undergoes partial denaturation and self-assembles into amyloid (in vitro) when subjected to a mild denaturation stress (e.g., pH 4.8). Incorporation of the V122I mutation into a folded monomeric variant of transthyretin reveals that this mutation does not destabilize the tertiary structure or alter the rate of amyloidogenesis relative to the wild-type monomer. The increase in the velocity of rate-limiting tetramer dissociation coupled with the lowered tetramer stability (increasing the mol fraction of folded monomer present at equilibrium) may explain why V122I confers an apparent absolute anatomic risk for cardiac amyloid deposition.

Chronic phospholamban (PLB)-sarcoplasmic reticulum calcium ATPase interaction is discussed as the critical calcium cycling defect in dilated cardiomyopathy. A study has used a genetic complementation strategy in a well-known mouse model of dilated cardiomyopathy. It is deficient in the cytoskeletal LIM protein, which is muscle-specific. Progressive defects in excitation-contraction coupling are related to enhancement of inhibition of SER-CA2a by PLB. Inhibition of PLB expression or PLB-SERCA2a interaction can prevent heat failure.

The vitamin A deficient (VAD) quail embryo lacks active retinoids, fails to express normally GATA-4, and develops a nonlooping heart tube morphogenetic defect that is a model for congenital cardiomyopathy. VAD quail embryos, or chick embryos depleted specifically for GATA factors, show in addition abnormal foregut development, characterized by apoptosis of the endoderm cells associated with presumptive myocardium during the process of heart tube formation. Exogenous retinoic acid or transplantation of normal chick embryo anterior endoderm is sufficient to rescue apoptosis as well as GATA-4 expression and results in normal development and heart tube morphogenesis. Normal posterior endoderm also contains retinoids but is unable to rescue the VAD defect. Our results indicate that a retinoid-dependent transcriptional program, mediated at least in part by GATA factors, is critical in presumptive foregut endoderm for normal heart tube morphogenesis. [C] 2000 Academic Press Key Words: cardiogenesis; GATA factors; chick; quail; vitamin A deficiency.