Transgenic models of myocardial dysfunction

Abstract

Transgenic Technology (TT), is an important tool in the molecular biology arena. It allows one to generate new strains of mice in which a genetic construct is expressed. The construct can be made with a promoter that allows for the targeted expression of a gene of interest to a given part of the cardiovascular system. By so doing, it is possible to modify a given physiologic function and to better understand the structural and functional relationships. This so-called "reverse physiology" is becoming extensively utilized in cardiac research. Another possibility is to use this technology to analyze which part of a promoter is responsible for the transcriptional regulation. In that case, the coding sequence is a gene not normally expressed in the tissue and is called the reporter. Mice are generally used for such a purpose because of their cost. Consequently the physiology of the mouse has been developed using microtechnologies.Several models of cardiac hypertrophy or tumors have been developed using genes encoding various transcriptional factors, such as oncoproteins or skeletal myogenic regulators. The overexpression of the two ~-Adrenergic Receptors (AR), did not generate hypertrophy, while that of al~-AR did. Myocardial function has been studied after disruption or overexpression of genes known to be vital to the functioning of the myocardium. Disruption of phospholamban results in increased relaxation and contractility. The overexpression of both the ~1-and ~2-AR increases basal contractility, which becomes insensitive to isoproterenol. We have also found in our laboratory that the enhanced ~I-AR model has an impaired heart rate variability without arrhythmias or shortening of the life span. An overexpression of Gs~ or ~-AR kinase does not have any inotropic effect per se, but results in an enhanced inotropic and chronotropic effect of isoproterenol. Such experiments have been the basis of new concepts in receptology. Several transgenic models of arterial hypertension with cardiac hypertrophy are now available. Most of them have been created by transgenic manipulations of the renin-angiotensin system. For the moment, there are only a few transgenic models of cardiac failure available.can synthesize DNA or RNA fragments and use them to make proteins or detect rapid changes in the cardiac or vascular structures. Soon after, molecular biologists could not resist the fascinating experiment inherent in introducing a new genetic material into germinal, autosomal, and even in adult cells. This was done in order to change genetic expression, with the ultimate goal of either permanently or transiently, modifying the phenotype of a cell, of a group of cells, and finally of an entire organism.Gene transfer technologies are currently a source of heated debate in cardiovascular research. These technologies offer promising areas for therapeutic approaches, such as the prevention of restenosis after coronary angioplasty. Nevertheless, the time when DNA can be a real drug is unpredictable. In contrast, these technologies, and ...

Differential protein expression during aging in ventricular myocardium of Fischer 344×Brown Norway hybrid rats

“…We identified two proteins with possible roles in diastolic dysfunction, both of which increased in abundance in stepwise fashion from 4 to 34 months: myosin regulatory light chain 2 (MLC-2) and parvalbumin. It has been reported that MLC-2 overexpression causes diastolic dysfunction (Palermo et al, 1995; Swynghedauw, 1996), thus the upregulation of MLC-2 we observed may play some role in impairing relaxation with age. The upregulation of parvalbumin, however, is most likely adaptive to diastolic dysfunction.…”

Proteome analysis in the assessment of ageing

“…Of the 46 differentially expressed proteins identified by MALDI-TOF-MS, 16 were associated with the regulation of apoptosis, including parvalbumin, desmin, heat shock protein 27, peroxiredoxin 6, and kallikrein, indicating an adaptive rather than pro-apoptotic alteration. The upregulation of parvalbumin, a calcium binding protein, may also be adaptive to diastolic dysfunction facilitating myocardial relaxation (Schmidt et al, 2005), while the age-related increase in myosin regulatory light chain 2 (MLC-2) potentially contributes to diastolic dysfunction (Swynghedauw, 1996). The age-related increase in the level of 2-oxoglutarate 5 dioxygenase 1 (lysyl hydroxylase 1) may promote the formation of hydroxylysine sites essential for the stability of the intermolecular collagen cross-links, therefore contributing to fibrosis and diastolic dysfunction.…”

The Federation of European Physiological Societies (FEPS)

“…For example, the knock-out of the neuronal isoform of nitric oxide (NO) synthase has quite a few consequences in terms of NO production, because of the compensatory expression (or re-expression) of new isoforms [9]. Fifth, transgenic technology has given rise to an incredibly large collection of new animal models, an unexplored treasure for generations of physiologists [6,10]! In addition, these strains are strains of genetically identical animals particularly suitable for physiological and pharmacological research.…”

“…There are a number of reasons for this. First, because mice are used commonly for transgenic technology, this has generated a lot of physiological investigations on mice, whereby, as we have learnt recently, mice are not small rats [6]! Second, gene transfer or gene knock-out frequently confirms or extends what we know or suspect already.…”