Dysregulated phenylalanine catabolism plays a key role in the trajectory of cardiac aging

Background: Aging myocardium undergoes progressive cardiac hypertrophy and interstitial fibrosis with diastolic and systolic dysfunction. Recent metabolomics studies shed light on amino acids in aging. The present study aimed to dissect how aging leads to elevated plasma levels of the essential amino acid phenylalanine (Phe) and how it may promote age-related cardiac dysfunction. Methods: We studied cardiac structure and function, together with Phe catabolism in wild-type (WT) and p21-/- mice (male; 2 to 24 months), the latter known to be protected from cellular senescence. To explore Phe's effects on cellular senescence and ectopic Phe catabolism we treated cardiomyocytes (primary adult rat or human AC-16) with Phe. To establish a role for Phe in driving cardiac aging, WT male mice were treated twice a day with Phe (200 mg/kg) for a month. We also treated aged WT mice with tetrahydrobiopterin (BH4; 10 mg/kg), the essential cofactor for the Phe-degrading enzyme phenylalanine hydroxylase (PAH), or restricted dietary Phe intake. The impact of senescence on hepatic Phe catabolism was explored in vitro in AML12 hepatocytes treated with Nutlin3a (a p53 activator), with or without p21-targeting siRNA or BH4, with quantification of PAH and tyrosine levels. Results: Natural aging is associated with a progressive increase in plasma Phe levels concomitant with cardiac dysfunction, whilst p21 deletion delayed these changes. Phe treatment induced premature cardiac deterioration in young WT mice, strikingly akin to that occurring with aging, whilst triggering cellular senescence, redox and epigenetic changes. Pharmacological restoration of Phe catabolism with BH4 administration or dietary Phe restriction abrogated the rise in plasma Phe and reversed cardiac senescent alterations in aged WT mice. Observations from aged mice and human samples implicated age-related decline in hepatic Phe catabolism as a key driver of elevated plasma Phe levels and showed increased myocardial PAH-mediated Phe catabolism, a novel signature of cardiac aging. Conclusions: Our findings establish a pathogenic role for increased Phe levels in cardiac aging, linking plasma Phe levels to cardiac senescence via dysregulated Phe catabolism along a hepatic-cardiac axis. They highlight Phe/PAH modulation as a potential therapeutic strategy for age-associated cardiac impairment.</p

Peripheral PDLIM5 expression in bipolar disorder and the effect of olanzapine administration

<p>Abstract</p> <p>Background</p> <p>One of the genes suggested to play an important role in the pathophysiology of bipolar disorder (BPD) is <it>PDLIM5</it>, which encodes LIM domain protein. Our main objective was to examine the effect of olanzapine treatment on <it>PDLIM5</it> mRNA expression in the peripheral blood leukocytes of BPD patients.</p> <p>Methods</p> <p>We measured the expression of <it>PDLIM5</it> mRNA from 16 patients with BPD Type I after 0, 4, and 8 weeks of treatment with olanzapine using quantitative real-time PCR. The Young Mania Rating Scale was used to evaluate the severity of manic symptoms in BPD patients. We also compared <it>PDLIM5</it> mRNA expression in treatment-naïve BPD patients with that in healthy control subjects.</p> <p>Results</p> <p>No significant difference was found in <it>PDLIM5</it> mRNA expression between patients before olanzapine treatment and following 4 and 8 weeks of treatment (<it>p</it>>0.05). Although we observed a significant reduction in the severity of manic symptoms in all BPD patients (<it>p</it><0.05), the effectiveness of the medication did not significantly correlate with the expression of <it>PDLIM5</it> mRNA (<it>p</it>>0.05). Interestingly, <it>PDLIM5</it> mRNA expression differed significantly between treatment-naïve BPD patients and healthy control subjects (<it>p</it>=0.002).</p> <p>Conclusion</p> <p><it>PDLIM5</it> mRNA expression did not appear to be a reflection of the efficacy of olanzapine in reducing the manic symptoms of BPD. The significant difference in expression of <it>PDLIM5</it> mRNA in the peripheral blood leukocytes of treatment-naïve BPD patients versus that of healthy control subjects, however, suggests that it may be a good biological marker for BPD.</p