Abnormal Gene Expression in the Hypertrophied Myocardium

9 November, 2011 (17:34) | Heart Diseases | By: Health news

Biochemical Changes

The pioneering work of Meerson,50 who first characterized the biochemical events that lead to myocardial deterioration and cell death in animals with acute aortic constriction, has provided an understanding of the cellular events in the overloaded heart that corresponds to the clinical observations made 75 years earlier by Osler. Meerson, like Osler, described three stages in the response of the heart to a sudden hemodynamic overload (Table 2). The first stage, which Meerson called transient breakdown, lasts several days and is characterized by acute heart failure with left ventricular dilatation, pulmonary congestion, and low cardiac output. The adaptive effects of cardiac hypertrophy then lead to a stage of stable hyperfunction, in which increased left ventricular mass raises cardiac output and alleviates the pulmonary congestion. However, in accord with Osler’s clinical observations, the compensation does not last but after several months is followed by progressive left ventricular failure. In this final stage, which Meerson called exhaustion and progressive cardiosclerosis, the hypertrophied heart undergoes progressive fibrosis and cell death, the circulatory manifestations of heart failure worsen, and the animals die.

Although the deterioration of the chronically overloaded heart, referred to here as the cardiomyopathy of overload, may be due in part to energy starvation (see above), there is growing evidence that molecular changes in the proteins synthesized in affected hearts also contribute to the downhill course usually seen in chronic congestive heart failure.

Abnormal Gene Expression in the Hypertrophied Myocardium

Since the pioneering work of Alpert and Gordon,53 who demonstrated that myosin ATPase activity is depressed in failing hearts, a growing number of molecular changes have been recognized in overloaded myocardial cells. This ability of the heart to alter its protein composition is a general process that can be viewed as a tonic control mechanism, which also adapts myocardial function to such long-term circulatory changes as aging and endocrine abnormalities.54 , 55 In addition, the remarkable ability of adjacent cells in the myocardium to express different genes gives rise to a “mosaicism” in which molecular heterogeneity in the proteins of the myocardium may help to achieve functional homogeneity, promoting efficient cardiac function.
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The appearance of abnormal isoforms of key myocardial proteins in the hypertrophic response to chronic overloading results from changes in gene expression that can arise from at least two different mechanisms. The first is the expression of different members of the multigene families that encode many important proteins of the heart. This mechanism is clearly seen in the rodent heart, in which the preferential synthesis of altered myosin isoforms adapts ventricular function to chronic abnormalities of the heart and circulation (see the next section). Variability in the proteins synthesized in the myocardium also results from alternative splicing, in which the exons of a single gene are assembled in different patterns as the nuclear RNA is processed to form messenger RNA. This mechanism allows the information contained in a single gene to encode the structures of several protein isoforms through variations in the manner by which the DNA sequence of the gene becomes transcribed into messenger RNA.