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Background: ␣Syn toxicity is triggered by oligomerization of ␣Syn, and its formation is partly regulated by PUFAs. Results: MPTP-induced neurotoxicity and ␣Syn oligomerization are attenuated in Fabp3 Ϫ/Ϫ mice. Conclusion:FABP3 is implicated in arachidonic acid-induced ␣Syn oligomerization and promotes dopaminergic cell death. Significance: FABP3 aggravates MPTP-induced neuronal toxicity and ␣Syn accumulation.␣-Synuclein (␣Syn) accumulation in dopaminergic (DA) neurons is partly regulated by long-chain polyunsaturated fatty acids. We found that fatty acid-binding protein 3 (FABP3, H-FABP), a factor critical for arachidonic acid (AA) transport and metabolism in brain, is highly expressed in DA neurons. Fabp3 knock-out (Fabp3؊/؊ ) mice were resistant to 1-methyl-1,2,3,6-tetrahydropiridine-induced DA neurodegeneration in the substantia nigra pars compacta and showed improved motor function. Interestingly, FABP3 interacted with ␣Syn in the substantia nigra pars compacta, and ␣Syn accumulation following 1-methyl-1,2,3,6-tetrahydropiridine treatment was attenuated in Fabp3 ؊/؊ compared with wild-type mice. We confirmed that FABP3 overexpression aggravates AA-induced ␣Syn oligomerization and promotes cell death in PC12 cells, whereas overexpression of a mutant form of FABP3 lacking fatty-acid binding capacity did not. Taken together, ␣Syn oligomerization in DA neurons is likely aggravated by AA through FABP3 in Parkinson disease pathology.Parkinson disease (PD) 2 is a common motor disorder affecting Ͼ1% of the population over 65 years of age worldwide (1). Histopathologic features of PD are the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of cytoplasmic protein aggregates, known as Lewy bodies (LBs) (2). ␣-Synuclein (␣Syn), a 140-amino acid protein, is associated with synaptic vesicles in presynaptic nerve terminals (3), and ␤-sheet fibrillar aggregates, including ␣Syn, are major components of LBs. ␣Syn accumulation is associated with progressive loss of DA neurons, implicating that activity in PD pathogenesis (4). In addition, duplication/triplication (5-7) and missense mutations (A53T, A30P, E46K, H50Q, and G51D) (8 -12) in the ␣Syn gene SNCA are linked to familial early onset PD, suggesting that the mutations accelerate ␣Syn aggregation and disease progression.␣Syn toxicity is triggered by oligomerization of ␣Syn in vitro (13) and in vivo (14), indicating that oligomerization underlies cytotoxic events in PD. However, mechanisms underlying ␣Syn oligomerization in DA neurons are unclear. Previous reports suggested that ␣Syn binds fatty acids, particularly long-chain polyunsaturated fatty acids (PUFAs) (15,16), and that ␣Syn oligomerization and the appearance of LB-like inclusions in cultured mesencephalic neuronal cells are enhanced by exposure to . In addition, abnormally high PUFA levels are observed in ␣Syn-transfected mesencephalic neuronal cells and in PD brains, whereas lower levels are seen in mice lacking ␣Syn (17, 18), suggesting that PUFA binding to ␣Syn is ...

Selective serotonin reuptake inhibitors (SSRIs) are known to reduce post-myocardial infarction-induced morbidity and mortality. However, the molecular mechanism underlying SSRI-induced cardioprotection remains unclear. Here, we investigated the role of σ1-receptor (σ1R) stimulation with fluvoxamine on myocardial hypertrophy and cardiac functional recovery. Male ICR mice were subjected to transverse aortic constriction (TAC) in the cardiac aortic arch. To confirm the cardioprotective role of fluvoxamine by σ1R stimulation, we treated mice with fluvoxamine (0.5 or 1 mg/kg) orally once per day for 4 wk after the onset of aortic banding. Interestingly, in untreated mice, σ1R expression in the left ventricle (LV) decreased significantly over the 4 wk as TAC-induced hypertrophy increased. In contrast, fluvoxamine administration significantly attenuated TAC-induced myocardial hypertrophy concomitant with recovery of σ1R expression in the LV. Fluvoxamine also attenuated hypertrophy-induced impaired LV fractional shortening. The fluvoxamine cardioprotective effect was nullified by treatment with a σ1R antagonist [NE-100 (1 mg/kg)]. Importantly, another SSRI with very low affinity for σ1Rs, paroxetine, did not elicit antihypertrophic effects in TAC mice and cultured cardiomyocytes. Fluvoxamine treatment significantly restored TAC-induced impaired Akt and endothelial nitric oxide synthase (eNOS) phosphorylation in the LV. Our findings suggest that fluvoxamine protects against TAC-induced cardiac dysfunction via upregulated σ1R expression and stimulation of σ1R-mediated Akt-eNOS signaling in mice. This is the first report of a potential role for σ1R stimulation by fluvoxamine in attenuating cardiac hypertrophy and restoring contractility in TAC mice.

Bhuiyan MS, Shioda N, Fukunaga K. Ovariectomy augments pressure overload-induced hypertrophy associated with changes in Akt and nitric oxide synthase signaling pathways in female rats. Am J Physiol Endocrinol Metab 293: E1606-E1614, 2007. First published September 18, 2007; doi:10.1152/ajpendo.00246.2007.-To elucidate the molecular mechanism underlying estrogen-mediated cardioprotection in left ventricular (LV) hypertrophy and remodeling, we analyzed myocardial hypertrophy as well as cardiac function and hypertrophyrelated protein expression in ovariectomized, aortic-banded rats. Wistar rats subjected to bilateral ovariectomy (OVX) were further treated with abdominal aortic stenosis. Effects on LV morphology and function were assessed using echocardiography, and expression of protein levels was determined by Western blot analysis. The heartto-body weight ratio was most significantly increased in the OVXpressure overload (PO) group compared with the OVX group and in the PO group compared with sham. The LV weight-to-body weight ratio was also significantly increased in the OVX-PO group compared with the OVX group and in the PO group compared with sham. The most significant increases in LV end diastolic pressure, LV developed pressure, and Ϯdp/dtmax were observed in the OVX-PO group compared with the OVX group and represent compensatory phenotypes against hypertrophy. Both endothelial nitric oxide (eNOS) synthase expression and activity was markedly reduced in the OVX-PO group, and protein kinase B (Akt) activity was largely attenuated. Marked breakdown of dystrophin was also seen in hearts of OVX-PO groups. Finally, significantly increased mortality was observed in the OVX-PO group following chronic isoproterenol administration. Our results demonstrate that rats subjected to ovariectomy are unable to compensate for hypertrophy, showed deteriorated heart function, and demonstrated increased mortality. Simultaneous impairment of eNOS and Akt activities and reduced dystrophin by ovariectomy likely contribute to cardiac decompensation during PO-induced hypertrophy in ovariectomized rats. estrogen; myocardial hypertrophy; nitric oxide synthase EPIDEMIOLOGICAL STUDIES SHOW that the incidence of cardiovascular disease is higher in men than in premenopausal women but increases in postmenopausal women (10). Sex differences in left ventricular (LV) hypertrophy and remodeling have also been observed in aging and pressure-overloaded human hearts (4). It is suggested that, because of reduced estrogen levels after menopause, women lose an important cardiovascular protective mechanism and are at greater risk of developing hypertension (1). Moreover, estrogen has multiple protective effects on the cardiovascular system (27). However, the role of estrogen in development of cardiac hypertrophy is poorly understood. Most animal models of heart failure indicate that females resist cardiac contractile dysfunction (8,11,34). The relationship of sex and hypertrophy-induced heart failure is complex and depends on the model/etiology of hy...

Background: An ER-associated chaperone protein, 1 receptor ( 1 R), regulates ER/mitochondrial Ca 2ϩ mobilization through the IP 3 receptor. Results: We identify a novel short splicing variant of 1 R, termed 1 SR, and demonstrate its dominant negative function. Conclusion: 1 SR interferes with 1 R function in mitochondrial Ca 2ϩ mobilization and ATP production under ER stress conditions. Significance: In contrast to 1 R function, 1 SR has detrimental effects on cell survival.