Genetic expression profiles during physiological and pathological cardiac hypertrophy and heart failure in rats

Abstract

Cardiac hypertrophy is a complex and nonhomogenous response to various stimuli. In this study, we used high-density oligonucleotide microarray to examine gene expression profiles during physiological hypertrophy, pathological hypertrophy, and heart failure in Dahl salt-sensitive rats. There were changes in 404/3,160 and 874/3,160 genes between physiological and pathological hypertrophy and the transition from hypertrophy to heart failure, respectively. There were increases in stress response genes (e.g., heat shock proteins) and inflammation-related genes (e.g., pancreatitis-associated protein and arachidonate 12-lipoxygenase) in pathological processes but not in physiological hypertrophy. Furthermore, atrial natriuretic factor and brain natriuretic protein showed distinctive changes that are very specific to different conditions. In addition, we used a resampling-based gene score-calculating method to define significantly altered gene clusters, based on Gene Ontology classification. It revealed significant alterations in genes involved in the apoptosis pathway during pathological hypertrophy, suggesting that the apoptosis pathway may play a role during the transition to heart failure. In addition, there were significant changes in glucose/insulin signaling, protein biosynthesis, and epidermal growth factor signaling during physiological hypertrophy but not during pathological hypertrophy. atrial natriuretic factor; brain natriuretic protein; insulin; apoptosis; microarray CARDIAC HYPERTROPHY is a complex response to various hypertrophic signals that promote the growth of cardiac myocytes. Multiple neurohumoral, hormonal, and mechanistic stimuli have been implicated in, and numerous interdependent pathways and molecules shown to be associated with, cardiac hypertrophy (10, 37). Accordingly, the responses of cardiac myocytes to different hypertrophic stimuli are not homogenous. Examples of stimulus-dependent hypertrophic responses can be found in both physiological and pathological hypertrophy. Exercise-induced cardiac hypertrophy is a good example of physiological hypertrophy, which is a favorable adaptive response of the heart to increases in bodily demand (8). In comparison, pathological hypertrophy is a maladaptive response to pathological stimuli, such as pressure or volume overload. These differences are particularly evident clinically, for pathological hypertrophy often progresses to heart failure, especially when pathological stimuli are persistent, whereas physiological hypertrophy usually does not. These examples support the notion that cardiac hypertrophies are not all the same, and suggest that stimulus-specific hypertrophic responses may be associated with distinct molecular changes (20,27).Previous studies of models of cardiac hypertrophy, using microarray technology, have yielded interesting but varied results (1,4,13,16,19,23,31,32,34,50,54). Studies of putative physiological stimuli showed increased expression of genes involved in the cell cycle, cell structure, intracellular signaling, protein s...

Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals

“…In this context, a number of genes altered by HS diet were normalized by PC including the myosin heavy-chain isoform switch characteristic of loaddependent hypertrophy (10,14). Changes in ␣-tropomyosin and in the NF-B pathway, which have been linked with ventricular hypertrophy (31,32), were also positively modified by PC.…”

“…To evaluate the effect of activated vitamin D on cardiac structure and function, we chose the previously characterized high-salt (HS)-induced model of hypertension and LVH in which Dahl salt-sensitive (DSS) rats develop LVH and signs of diastolic dysfunction as early as 6-8 weeks after HS exposure (9,10). Organ weights were adjusted to the tibial length (Table 1).…”

Response of caspase-independent apoptotic factors to high salt diet-induced heart failure

“…The experimental procedures of the exercise-induced physiologic cardiac hypertrophy and the HS diet-induced pathologic heart failure were previously described [11,12]. In brief, at 6 weeks of age, rats in the exercise group exercised daily on a rodent treadmill (Columbus Instruments, Columbus, OH) following a modified training program which comprised a 3-wk progressive intensity-increasing period followed by a 3-wk maintenance period [13,14].…”

“…For HS diet and failure groups, animals were fed a 6% sodium chloride diet at 6 weeks of age to induce pressure-overload pathologic cardiac hypertrophy and subsequent heart failure. Animals developed pathologic cardiac hypertrophy by 12 weeks of age (6 weeks of HS diet) and clinical evidence of heart failure following 13-15 wk of HS diet [11,12]. All animals died after 15-17 weeks of HS diet.…”

“…Echocardiography was performed according to previously described protocol [11,12]. Rats were anesthetized with an intraperitoneal injection of ketamine HCl (50 mg/kg) and xylazine (10 mg/kg).…”