The majority of work completed to date on ODC and cardiac hypertrophy has measured the effects of altered ODC activity only on the polyamines, which are downstream products of the ODC reaction. However, the ODC protein is part of a more complex signaling cascade (Fig. 1). The ODC substrate ornithine is produced in all cells by the activity of arginase, which catalyzes the conversion of L-arginine to L-ornithine and urea (39). Arginase exists as two isoforms, with arginase I targeted to the cytoplasm and arginase II to the mitochondria (39). ODC is extramitochondrial, whereas ornithine may be located in the mitochondria or cytoplasm (Fig. 1). L-arginine is also the substrate for NO synthases (NOS). All three NOS isoforms catalyze the synthesis of NO and L-citrulline from L-arginine (40). Thus the conversion of L-arginine into L-ornithine by arginase limits the availability of L-arginine as a precursor of NO and shifts the equilibrium between NOS and ODC toward polyamine biosynthesis (41). The activity of arginase is therefore thought to play a regulatory role in the biosynthesis of both NO and polyamines (41).
NO production is involved in a large number of physiological and pathophysiological functions in animal tissues, and the cardiovascular system is dramatically affected by its availability. Among its actions, NO is responsible for endothelium-mediated vasorelaxing tone, prevents platelet aggregation and adhesion to the vessel wall, and is the mediator of parasympathetic neurovegetative tone in the myocardium. In addition, several reports have pointed out the antiproliferative effect of NO in smooth muscle cells in the patho-genesis of atherosclerosis (42) and the antihypertrophic potential of NO in the heart (43).
In agreement with their opposing effects on cell proliferation, polyamines can inhibit NOS activity and NO-mediated effects (44,45). In addition, NO and its intermediate NG-hydroxy-L-arginine have been identified as inhibitors of ODC and polyamine-mediated pathways (46). Other studies have shown that NG-hydroxy-L-arginine inhibits arginase activity (47) and limits cell proliferation (48) in several biological systems.
As with ODC induction, NO deficiency has also been linked to the development of cardiac hypertrophy using mouse models, as shown in Table 1 (43). NO has been shown to diminish the P-adrenergic response in cardiomyocytes (49), and overexpression of NOS 3 in the heart using the preproendothelin-1 promoter was found to attenuate cardiac hypertrophy in response to isoproterenol, as measured by the decreased ratio of heart weight to body weight and myocyte cross-sectional area (50). ANF-upregulation in response to isoproterenol was also inhibited in NOS 3 transgenic mice. Another trans-genic NOS 3 line that made use of the native NOS 3 promoter to produce moderate elevations of protein and preserve transcriptional regulation showed a dramatic increase in survival with reduction of pulmonary edema and improved cardiac function in NOS 3-overexpressing mice subjected to infarct-induced congestive heart failure (51).
The findings described support strongly the differential regulation of NO and polyamine biosynthesis through the availability of arginine. Consistent with this idea is the observation that when cardiac hypertrophy was induced in MHC-ODC mice with isoproterenol, arginase activity was induced dramatically, whereas activity in littermate controls was below the limit of detection (29). The transgenic phenotype is also characterized by a twofold upregulation of NOS 3 protein in the heart (29). Changes in
Fig. 1. The polyamine and arginine metabolic pathways.
Fig. 1. The polyamine and arginine metabolic pathways.
L-arginine availability may therefore contribute to differential regulation of NO and polyamine biosynthesis in MHC-ODC mice. Little is known about the levels of the polyamines or their enzymes in the hearts of NOS knockout mice or mice with cardiac-specific NOS overexpression. However, the results obtained with MHC-ODC mice indicate that these questions are worth pursuing.
The overproduction of polyamines, induction of arginine-metabolizing enzymes, and activation of P-adrenergic pathways may interact through several possible mechanisms. For example, activation of P-adrenergic receptors causes Ca2+ mobilization through phosphorylation of the L-type calcium channel by the cAMP-dependent protein kinase A, and also through direct coupling of stimulatory guanosine 5'-triphosphate regulatory protein to calcium channel activation (19). It has been suggested that polyamines may play a role in stimulation of Ca2+ influx in rat myocytes in the presence of isoproterenol (52). Thus the positively charged polyamines, particularly the diamine putrescine, may affect Ca2+ mobilization in response to P-adrenergic receptor activation. It is also known that NO inhibits L-type Ca2+ channels (53), and it has been shown that NOS 3 localizes to caveolae, where it is compartmentalized with P-adrenergic receptors and L-type Ca2+ channels (54). Therefore, the increase in NOS 3 in the hearts of MHC-ODC mice may represent an attempt to supply an adaptive counterresponse to the hypertrophic stimulus. This is also suggested by evidence in the literature pointing to the ability of NO to downregulate ODC activity (46) and to blunt the hypertrophic potential of a variety of myocardial stressors (43).
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