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Chapter 4: PRINCIPLES OF MOLECULAR CARDIOLOGY MOLECULAR BASIS FOR CELLULAR GROWTH Patterns of Growth (Hyperplasia, Hypertrophy, and Constitutive)

The molecular genetic basis for growth is somewhat distinct,5!,52 depending on when in the life of the organism it occurs, and may be divided into four phases: the embryonic phase of development and cellular differentiation (to be discussed later) occurring in utero, the rapidly growing phase prior to and during puberty, the normal constitutive maintenance growth throughout life, and compensatory growth in response to stimuli such as exercise or injury. Growth may be associated with an increase in the number of cells (hyperplasia) or just an increase in the size (hypertrophy) or just replacement of proteins as they are catabolized with no change in the number of cells, their size, or function (constitutive growth). During early development in the fetal and embryonic stages, practically all cells proliferate as well as increase in size and are said to be in cell cycle (Fig. 4-19). Throughout this process, certain cells drop out of cell cycle, cease proliferating, and undergo the process of differentiation. At birth or within weeks thereafter, certain cells of organs, such as the heart and brain, lose their ability to proliferate, and growth is restricted to the constitutive or hypertrophic type. Some cells undergo programmed cell death, called apoptosis. Many of the genes responsible for embryonic development subsequently downregulate after birth. Conversely, genes that code for proteins serving specialized functions in the differentiated cell are inhibited in the proliferating, undifferentiated cell and are only expressed on differentiation. For example, the muscle cell, on differentiation, downregulates the gene that encodes for BB creatine kinase and upregulates the gene that encodes for MM creatine kinase. Similarly, upregulation occurs for the genes that encode for myosin, actin, and other sarcomeric proteins essential to the contractile performance of the cell. It is estimated that the human body has a total of 1014 cells but only about 200 different types defined by their specific function. The specialized functions of a cell are determined by the repertoire of genes expressed in that particular cell.

The Artery Four Steps

Figure 4-19: The cell cycle in a mammalian cell having a generation time of 16 h. The three phases spanning the first 15 h or so-the G1 (first gap) phase, and S (synthetic) phase, and the G2 (second gap) phase-make up the interphase, during which DNA and other cellular macromolecules are synthesized. The remaining hour is the M (mitotic) phase, during which the cell actually divides.

Figure 4-19: The cell cycle in a mammalian cell having a generation time of 16 h. The three phases spanning the first 15 h or so-the G1 (first gap) phase, and S (synthetic) phase, and the G2 (second gap) phase-make up the interphase, during which DNA and other cellular macromolecules are synthesized. The remaining hour is the M (mitotic) phase, during which the cell actually divides.

In the adult heart, most of normal growth is constitutive. It is estimated that most of the proteins of the heart are replaced every 5 days, except collagen, which replaces itself every 120 days; with hypertrophy, however, the half-life of collagen is only 17 days. Thus, in humans, the heart is replaced about every 3 weeks. It is estimated that all human functions are determined by about 67,000 genes, and about 10,000 genes (proteins) are required to maintain basal cellular integrity of a particular organ, except the brain, which requires about 20,000 genes. Thus, maintaining normal cellular homeostasis is a dynamic growth process. For example, in every second of a human being's life, more than a million trillion hemoglobin molecules are synthesized.

Growth Factors and Receptors Underlying the Growth Response

Normal and pathologic growth is initiated by multiple factors. Several of the circulating hormones, such as growth hormone, thyroxine, mineralocorticoids, glucocorticoids, and angiotensin II, act as growth factors. Growth factors such as transforming growth factor beta (TGFP) and the fibroblastic growth factors (FGFs) are produced locally, released into the immediate environment, and mediate their effect on growth through what is termed paracrine or autocrine mechanisms. Paracrine refers to a growth factor that is secreted and affects the growth of adjacent cells. Autocrine refers to a growth factor that binds to the receptors of the same cell from which it was produced and secreted. Intracrine refers to a growth factor that induces growth in the same cell from which it was produced without being secreted. An external stimulus that influences growth is detected by a receptor that usually sits on the cell's surface as an intramembrane receptor and is relayed through several signaling or transducing proteins to the nucleus of the cell, where the ultimate effector molecule is a transcription factor (Table 4-2). The effector molecule also may affect growth through regulation of translation. The latter, however, is usually more transient, whereas a sustained change in growth almost always is mediated through transcription. The signaling proteins usually involve kinases and phosphatases, which through phosphorylation transfer ATP to amplify the signal and by dephosphorylation decrease it or in some way alter it Fig. 4-20). Regulation of protein synthesis also may result from altered stability of mRNA. The growth response to circulating hormones or locally produced growth factors occurs several hours after the initial stimulation and is more likely to occur if two or more growth factors have been activated (see Chap. 5). In the case of the heart, a common signal is increased intraventricular pressure, which results in compensatory hypertrophy (see Chap. 5).

Table 4-2: Cascade for Relaying Growth Signals

Receptor i

Coupling protein

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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