Altered Polyamines in the Hypertrophic Phenotype

Initial observations pointing out the relationship between polyamines and cardiac hypertrophy date back more than 30 yr. In these studies, increases in polyamines were found in the ventricular myocardium of animals in which hypertrophy was induced by ascending aortic stenosis (5), stress (6), intense muscular exercise (7), or the P-adrenergic receptor agonist isoproterenol (8). The rise in polyamine content was accompanied by increased histone acetylation (9), and increased rates of both RNA synthesis (7,9) and protein synthesis (10). Inhibition of polyamine synthesis decreased histone acetylation and RNA transcription, and this effect was reversed by spermine (11). Later studies also implicated increased spermidine and spermine in hypertension and cardiac hypertrophy in a rat angiotensin II infusion model (12).

A hallmark of the hypertrophic phenotype induced by either pressure overload or agonist administration is immediate early gene expression, including c-fos, c-jun, c-myc, and ODC (2,13). ODC gene expression is accompanied by induction of ODC protein and activity. Increased ODC activity has been shown to occur quite rapidly in both mouse and rat models in response to various agents that induce a pathological cardiac hypertrophy, including thyroxine (14), the P-adrenergic agonists isoproterenol (P1 and P2) and clenbuterol (P2) and the aj-adrenergic agonists phenylephrine and meth-oxamine (15-17). Another study has reported that ODC induction in response to isoproterenol depends upon increased transforming growth factor-P activity, both in primary myocyte culture and in isolated, perfused mouse hearts (18).

Administration of a-difluoromethylornithine (DFMO), a suicide inactivator of ODC, reduced polyamine content and attenuated isoproterenol- and clenbuterol-induced cardiac hypertrophy (15,16,18). Another inhibitor of ODC, a-methylornithine, also inhibited both ODC induction and development of a hypertrophic phenotype in cardiac myocytes with high transforming growth factor-P activity (18). Interestingly, DFMO did not prevent thyroxine-induced hypertrophy (13,14), and a-methylornithine did not attenuate phenylephrine-induced hypertrophy (18). These results suggest ODC-dependent and ODC-independent processes leading to the hypertrophic state, depending on the inducer.

The induction of ODC activity in response to P-adrenergic agonists has been extensively studied in recent years. The P-adrenergic pathway is a critical point of hormonal control of cardiac contractility in both normal and failing hearts. Although the mechanism of induction of ODC during P-agonist-induced hypertrophy is still unknown, the promoter of the ODC gene contains a cyclic adenosine monophosphate (cAMP)-response element, and the P-adrenergic receptor pathway activated by agonists such as isoproterenol involves the stimulatory guanosine 5'-triphosphate regulatory protein (Gs), activation of adenylyl cyclase, and accumulation of cAMP (19,20). ODC activity can also be induced in myocyte culture by dibutyryl-cAMP (18).

Several studies have suggested that the induction of ODC in response to P-adrenergic stimulation is primarily through P2-adrenergic receptors, which are a minor component of the P-adrenergic receptors in the heart, but may become more important in the failing heart (reviewed in ref. 19). Our studies using isoproterenol and the P1-receptor specific antagonist atenolol suggest that both P1 and P2 receptors contribute to the hypertrophy seen in the hearts of a-myosin heavy chain (MHC)-ODC transgenic mice, as discussed in the following section (21). In addition, it has been shown that cardiac hypertrophy resulting from treatment with the P2-specific agonist clenbuterol results in an accumulation of polyamines in the heart, which can be reversed by DFMO. ODC induction by isoproterenol both in vivo and in primary myocyte culture could also be prevented by P2-receptor specific antagonists (15,18,22).

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