Abnormal Membrane Assembly
Abnormalities in the sarcoplasmic reticulum of the failing heart, in which slowed calcium uptake may contribute to impaired relaxation (see “Relaxation Abnormalities”), appear to reflect a reduced concentration of calcium-pump ATPase molecules in this internal membrane, rather than the expression of an altered isoform of the large molecule.82 , 83 Another example of altered membrane assembly in the overloaded heart is suggested by a recent report that the density of voltage-sensitive calcium channels may be increased in the atria of patients with hypertrophic cardiomyopathy.84 This report extends to humans a genetic cardiomyopathy previously described in the Syrian hamster. However, since the density of calcium channels was not found to be altered in renal-hypertensive rats, the increased number of calcium channels described in the human and hamster cardio-myopathies may be related to underlying genetic abnormalities rather than to the hypertrophic response itself.
Role of Proto-oncogenes
Proto-oncogenes, which play a major part in regulating growth and differentiation, provide a remarkably complex control of the many steps between signal recognition and altered gene expression. By allowing protein synthesis to respond to a wide range of influences both outside and within the cells of the heart, the proto-oncogenes regulate the hypertrophic process and may have a pathogenetic role in the cardiomyopathy of overload.
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The proto-oncogenes exert their regulatory effects by encoding a variety of growth factors and their receptors, intracellular transducers, modulators, amplifiers, and DNA-binding factors involved in the control of RNA transcription. Although this field is still in its infancy, it is apparent that hemodynamic overloading increases the expression of c-fos and c-myc, proto-oncogenes that encode short-lived nuclear proteins that promote and regulate cell proliferation and differentiation. In the overloaded heart, the activation of these proto-oncogenes, along with the heat-shock protein gene HSP 70, resembles the early mitogenic responses to a variety of growth factors in other cell types and may be part of a general adaptive response to stress.
The induction of c-fos and c-myc, which occurs within an hour of acute pressure overload, is transient and precedes the expression of fetal isoforms of several contractile proteins and atrial natriuretic factor.76 Thus, in addition to stimulating the overall rate of protein synthesis, proto-oncogenes may control alterations in specific protein isoforms synthesized by the overloaded heart.
Although the roles of the proto-oncogenes in activating and reprogramming gene expression in the overloaded heart remain to be fully elucidated, rapid progress in this important field promises new insights into the pathogenesis of the cardiomyopathy of overload.