The hallmark of cardiac hypertrophy is a net increase in protein synthesis above protein degradation. Under normal circumstances, these two processes are matched and result in nitrogen balance. Since the average half-life of cardiac proteins is 5 days, the composition of the adult heart is regenerated approximately every 3 weeks. The more rapid rate of cardiac growth in response to increased hemodynamic load could result from an augmentation in either the efficiency or the capacity of protein synthesis or a combination of the two.44,45 Efficiency of protein synthesis is usually measured as moles of amino acid incorporated per milligram of cellular RNA per hour; capacity is assessed by determining the number of milligrams of RNA per gram of tissue. Experiments in a variety of systems indicate that the critical determinant for cardiac hypertrophy is an increased capacity for protein synthesis, which is mediated by augmented ribosomal content. Protein degradation appears to be modestly increased in cardiac hypertrophy and may play a critical role in the distinctive geometry of the ventricles in response to pressure or volume overloading, regression of hypertrophy, and cardiac atrophy.46,47 The mechanisms for protein degradation in the heart involve the activation of both lysosomal and cytosolic proteases. Posttranslational processes are increasingly being recognized as important factors in the production of the cardiac phenotype in cardiac hypertrophy and failure.3548
In addition to increased total protein content, cardiac hypertrophy is characterized by alterations in the relative abundance and isoform composition of the cardiomyocyte contractile, regulatory, and calcium-cycling proteins and other subcellular constituents. These processes provide an additional degree of plasticity for the heart to adapt to changing functional requirements. It is clear that there is considerable species specificity in the capacity for isoform switching. In small mammals with rapid heart rates, such as mice and rats, imposition of a pressure overload produces a transcriptionally mediated shift from the 0(- to the ft-MHC and from cardiac to skeletal O-actin.49'51 Q-Myosin has a three- to sevenfold greater ATPase activity than ^-myosin. The greater abundance of ft-MHC in response to pressure overload in small animals increases the efficiency of force development by producing the same absolute muscle tension at a slower rate.52 Despite identical cardiac muscle mechanics in response to hypertrophy, large animals with slower heart rates, including humans, possess ft-MHC almost exclusively throughout embryogenesis and postnatal development.53 It is possible that, in higher mammalian species, altered myosin ATPase in response to pressure-overload hypertrophy may be mediated in part by a posttranslationally produced low-molecular-weight variant of the ft-MHC or isoform shifts in other myofibrillar proteins. For example, cardiac isoforms exist for essential and regulatory light chains, troponin (I, C, and T), tropomyosin, and the sarcolemmal Na+, K+-ATPase. Isoform switching of each of the components of the cardiomyocyte has been reported in hypertrophy and failure, but the functional significance of this has been unclear. The ability to ablate or overexpress these isoforms in genetically engineered mice will more clearly elucidate their role in the normal and hypertrophied heart.
Although cardiomyocytes make up the bulk of cardiac mass by volume, they are tethered in an extensive extracellular network of collagen and other structural proteins, including fibronectins and proteoglycans. The extracellular and intracellular myofibrillar scaffolding is a critical determinant of cardiac shape during normal and pathologic cardiac growth.54-56 Collagen is synthesized principally by fibroblasts but also by vascular smooth muscle cells in response to a variety of pathologic stimuli, including increased oxidative and mechanical stress, ischemia, and inflammation. Most of the molecules and signal transduction pathways operant in cardiomyocyte growth play a role in hyperplasia of fibroblasts and in the elaboration of collagen. The resultant fibrosis produces altered myocardial stiffness and arrhythmogenesis in ischemic heart disease, cardiac hypertrophy, and congestive heart failure. Collagen synthesis is continuously and variably offset by extracellular matrix resorption mediated by matrix metalloproteinases (MMPs). The activity of these enzymes is increased in dilated cardiomyopathy. Conversely, the activity of a class of enzymes known as tissue inhibitors of matrix metalloproteinases (TIMPs) is reduced in this setting. The resultant excessive collagenolyses may induce myofibrillar slippage and contribute to the dilated thin-walled chamber geometry that characterizes acute and chronic heart failure. This process has been termed chamber remodeling by clinicians.57
Cardiomyocytes are tethered to the extracellular matrix by membrane-spanning proteins called integrins. The extracellular portion of these molecules binds to fibronectins in the extracellular matrix while the cytoplasmic domain is associated with a nonreceptor tyrosine kinase called focal adhesion kinase (FAK).58 Downstream targets for FAK phosphorylation are the SRC kinases src and fyn. This pathway is differentially activated by mechanical stretch ischemia and oxidative stress in the myocardium and provides an additional mechanism for altered growth during pathologic conditions.59 Perimyocyte extracellular proteins such as dystrophin and dystrophin-related proteins contribute to normal cardiogenesis; when altered in abundance, they can produce a cardiomyopathy in Duchenne's muscular dystrophy and some familial cardiomyopathies, respectively (see Chap. 62).
The cardiomyocyte cytoskeleton is the intracellular scaffolding that provides a framework for the orderly arrangement of sarcomeres in striated cardiac and skeletal muscle. Titin-the third most abundant protein in the heart-desmin, and vinculin have differing intracellular spatial distributions that contribute to resting tension of cardiac muscle. The amount and polymerization status of the proteins that make up the microtubular network of the cardiomyocyte cytoplasm (tubulin and f> actin) are important determinants of the viscous properties of heart muscle and contribute to altered cardiac function in pathologic states.6061
Cardiac hypertrophy and failure are associated with changes in the relative abundance of the various intra- and extracellular structural proteins. All forms of cardiac hypertrophy are associated with increased collagen deposition in the extracellular matrix, which contributes to the observed alterations in passive chamber and muscle properties. Pressure overload (but not volume overload) hypertrophy has been associated with changes in the levels of the cytoskeletal proteins titin, desmin, and tubulin. Depolymerization of tubulin with colchicine reversed abnormalities in cardiac function in feline right ventricular hypertrophy but not in guinea pig left ventricular hypertrophy.60,61
Cardiomyocyte membrane depolarization is initiated by the intracellular movement of sodium through its ion channel, while repolarization is achieved by the extracellular movement of potassium via a family of sarcolemal K+ channels. Membrane depolarization enhances the transmembrane conductance of calcium through a dihydropyridine-sensitive l-channel. The resultant increase in cytosolic calcium concentration permits binding of this cation to the ryanodine receptor on the surface of the sarcoplasmic reticulum. This process results in release of calcium from sarcoplasmic reticulum stores and further elevation of cytosolic calcium concentrations. The resultant hundredfold elevation of calcium permits binding to the myofilament regulatory protein troponin C. Calcium binding to troponin C promotes a steric movement of troponin I away from the actin binding site on the myosin molecule. This permits actin-myosin cross-bridge formation and resultant tension development. The activity of troponin I can be modulated via phosphorylation by protein kinase A and C, while the affinity of troponin C for calcium is altered by intracellular pH. These processes may result in substantial alteration of myofilament calcium. Energy for cross-bridge cycling is produced by hydrolysis of ATP via myosin ATPase. Calcium is released from troponin C and resequestered into the sarcoplasmic reticulum by a specific SR-ATPase. The activity of this enzyme is inhibited by the phosphoprotein phospholamban. Phosphorylation of phospholamban by cAMP (PKA)-dependent protein kinases, protein kinase C, or calcium-calmodulin-dependent protein kinase results in disinhibition and resultant enhancement of calcium uptake in the SR. Steady-state sarcoplasmic reticulum calcium content is determined by the abundance of the anionic storage proteins calsequestrin and calreticulum. Reequilibration of cytosolic sodium and potassium levels produced by the depolarization and repolarization cycle is facilitated by the activity of the sarcolemmal Na+,K+-ATPase. Extrusion of transarcolemmal mediated calcium influx is mediated by the coordinated interplay between the membrane situated Na+-H+ and Na+-Ca2+ exchangers. Isolated changes in the stoichiometry between the sarcoplasmic reticulum ATPase and its inhibitor, phospholamban, have been demonstrated to have functional significance in genetically engineered mice. Targeted ablation of phospholamban enhanced cardiac inotropic and lusitropic function, whereas cardiac-specific overexpression produced the opposite result.62,63
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