Polyamine metabolism and function in the heart

Flamigni, Flavio; Rossoni, Carmen; Stefanelli, Claudio; Caldarera, Claudio Marcello

doi:10.1016/s0022-2828(86)80977-4

Cited by 50 publications

(20 citation statements)

References 62 publications

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“…In addition, our data also suggest a possible involvement of polyamines in some pathological forms of apoptosis. Cardiac hypertrophy, either pharmacologically induced or consequent to hypertension, is characterized by a large and prolonged increase in polyamine level [4][5][6], and is coupled to excessive apoptosis [46,47]. The abnormal accumulation of polyamines in cells stimulated to growth, but which cannot divide, may contribute to induction of apoptosis by causing the release of cytochrome c that could trigger caspase activation directly or by lowering the threshold of sensitivity to other pro-apoptotic stimuli.…”

Section: Discussionmentioning

confidence: 99%

“…Much is known about the biosynthesis, degradation and transport of polyamines [1][2][3], but despite several decades of extensive research, their function in cellular physiology remains unsettled, and the only established function of polyamines is their absolute requirement for cell growth [1,2]. In the heart, polyamine metabolism is affected strongly by numerous factors, both physiological and pathological, that influence cardiac function and growth [4]. An increase in heart polyamines is correlated, in particular, with hypertension [5], and, in general, with cardiac hypertrophy [4,6].…”

Section: Introductionmentioning

confidence: 99%

“…In the heart, polyamine metabolism is affected strongly by numerous factors, both physiological and pathological, that influence cardiac function and growth [4]. An increase in heart polyamines is correlated, in particular, with hypertension [5], and, in general, with cardiac hypertrophy [4,6].…”

Section: Introductionmentioning

confidence: 99%

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Polyamines directly induce release of cytochrome c from heart mitochondria

Stefanelli

Stanic

Zini

et al. 2000

Biochemical Journal

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Cytochrome c release from mitochondria to the cytosol represents a critical step in apoptosis, correlated to the activation of the caspase cascade. In this report, we show that addition of micromolar concentrations of polyamines to isolated rat heart mitochondria induces the release of cytochrome c. Spermine, which is effective at concentrations of 10-100 μM, is more potent than spermidine, whereas putrescine has no effect up to 1 mM. The release of cytochrome c caused by spermine is a rapid, saturable and selective process that is independent of mitochondria damage. Spermine, unlike polylysine, is able to release a discrete amount of cytochrome c from intact, functional mitochondria. The cytochrome c-releasing power of spermine is not affected by cyclosporin A, differently from the effect of permeability transition inducers. In a cardiac cell-free model of apoptosis, the latent caspase activity of cytosolic extracts from cardiomyocytes could be activated by cytochrome c released from spermine-treated heart mitochondria. These data indicate a novel mechanism of cytochrome c release from the mitochondrion, and suggest that prolonged and sustained elevation of polyamines, characteristic of some pathologies such as heart hypertrophy, could be involved in the development of apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Polyamines directly induce release of cytochrome c from heart mitochondria

Stefanelli

Stanic

Zini

et al. 2000

Biochemical Journal

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“…7,8 In the field of cardiac physiology, it has long been known that agonist activation of the β-adrenergic receptor results in a rapid rise in ODC activity with a corresponding increase in the concentration of PAs in cardiac myocytes. 9,10 The β-adrenergic agonist isoproterenol induces rapid hypertrophy of hearts of transgenic mice overexpressing ODC. 11 Thus, PAs are recognized as ubiquitous metabolites with profound effects on cell and systems physiology and are molecules of current interest in various disease processes.…”

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confidence: 99%

Sensitivity of cloned muscle, heart and neuronal voltage-gated sodium channels to block by polyamines

Cummins

Moczydlowski

2012

Channels

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Spermidine and spermine, are endogenous polyamines (PAs) that regulate cell growth and modulate the activity of numerous ion channel proteins. In particular, intracellular PAs are potent blockers of many different cation channels and are responsible for strong suppression of outward K + current, a phenomenon known as inward rectification characteristic of a major class of K IR K + channels. We previously described block of heterologously expressed voltage-gated Na + channels (Na V ) of rat muscle by intracellular PAs and PAs have recently been found to modulate excitability of brain neocortical neurons by blocking neuronal Na V channels. In this study, we compared the sensitivity of four different cloned mammalian Na V isoforms to PAs to investigate whether PA block is a common feature of Na V channel pharmacology. We find that outward Na + current of muscle (Na V 1.4), heart (Na V 1.5), and neuronal (Na V 1.2, Na V 1.7) Na V isoforms is blocked by PAs, suggesting that PA metabolism may be linked to modulation of action potential firing in numerous excitable tissues. Interestingly, the cardiac Na V 1.5 channel is more sensitive to PA block than other isoforms. Our results also indicate that rapid binding of PAs to blocking sites in the Na V 1.4 channel is restricted to access from the cytoplasmic side of the channel, but plasma membrane transport pathways for PA uptake may contribute to long-term Na V channel modulation. PAs may also play a role in drug interactions since spermine attenuates the use-dependent effect of the lidocaine, a typical local anesthetic and anti-arrhythmic drug.

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“…During the last two decades the interest in polyamines has considerably increased because of their clinical importance, as they can regulate heart muscle contractility, for example [7], and as their concentration is markedly enhanced in organs undergoing carcinogenesis [S]. However, up to now it is not known in general to which structures, apart from nucleic acids, polyamines are bound in a living cell and, in particular, what the mechanism is of their interaction with proteins.…”

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confidence: 99%

Complexes of the polyamines spermine, spermidine and putrescine with α‐lactalbumins

Morozova

Desmet

Joniau

1993

European Journal of Biochemistry

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The effects of polyamines on the spectral properties and thermal stability of different a-lactalbumins were measured. Addition of millimolar concentrations of spermine to the Ca2+-free (apo) form of bovine or goat a-lactalbumin resulted in spectral shifts, in both the far-and near-ultraviolet ranges, similar to those induced by Ca2+ binding. Fluorescence emission spectra of tryptophan residues underwent a pronounced blue shift, concomitant with a decrease in quantum yield. Also, in the presence of spermine, thermal stability was increased. In contrast, in the case of human and to some extent also equine a-lactalbumin, the shifts of the CD and fluorescence spectra and the thermal denaturation curves were in the opposite direction.Direct competition of spermine with Mn2+ could be observed for binding to the Ca*+ site of bovine a-lactalbumin. As the main binding mode of spermine showed a 1 : 1 stoichiometry [ K , = (2+0.5)X104M-'], we have assumed that binding occurs primarily at this site with one of the distal ammonium groups. In order to accommodate the remaining positively charged ammonium groups of spermine, a binding model was constructed by computer modeling, based on the atomic coordinates of both interacting species. This model makes use of the cluster of negatively charged glutamate residues present in the N-terminal sequence of bovine a-lactalbumin, sterically close to the CaZ ' site. The spermine molecule could be nicely fitted in a space delineated by the Ca'+ site, on the one hand, and Glul, Glu7 and Glull, on the other. Our model, which has been extended to the shorter polyamines spermidine and putrescine, is able to fully account for the observed stabilization of bovine (and goat) a-lactalbumins against thermal denaturation, and for the observed CD and fluorescence spectral shifts. It also explains why human (and equine) a-lactalbumin behave differently.

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Polyamine metabolism and function in the heart

Cited by 50 publications

References 62 publications

Polyamines directly induce release of cytochrome c from heart mitochondria

Polyamines directly induce release of cytochrome c from heart mitochondria

Sensitivity of cloned muscle, heart and neuronal voltage-gated sodium channels to block by polyamines

Complexes of the polyamines spermine, spermidine and putrescine with α‐lactalbumins

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