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Malaysiana 49(2)(2020): http://dx.doi.org/10.17576/jsm-2020-4902-14
Tocotrienol-Rich
Fraction Modulates Cardiac Metabolic
Profile Changes in
Isoprenaline-Induced Myocardial Infarction Rats
(Fraksi Kaya Tokotrienol
Memodulasi Perubahan Profil Metabolisma Jantung pada Tikus Infarksi Miokardium
Aruhan Isoprenalin)
KHAIRUL ANWAR ZARKASI1,4,
SATIRAH ZAINALABIDIN2, TAN JEN-KIT1, NUR HALEEDA HAKIMI1,
NUR ZULIANI RAMLI3,4 & ZAKIAH JUBRI1*
1Department of Biochemistry, Faculty of Medicine, UKM Medical Centre, Universiti
Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur,
Federal Territory, Malaysia
2Programme of Biomedical Science, Centre for Health and Applied Sciences, Faculty
of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz,
50300 Kuala Lumpur, Federal Territory, Malaysia
3Department of Anatomy, Faculty of Medicine, UKM Medical Centre, Universiti
Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur,
Federal Territory, Malaysia
4Department of Biomedical Sciences and Therapeutics, Faculty of Medicine and
Health Sciences, Universiti Malaysia Sabah, Jalan UMS, 88400 Kota Kinabalu,
Sabah, Malaysia
Diserahkan: 12 Mei 2019/Diterima: 24 Oktober 2019
ABSTRACT
In myocardial infarction (MI), the
occurrence of energy depletion, oxidative stress, and decreased amino acids
metabolism alter tissue metabolites. Evidence has shown that tocotrienol-rich
fraction (TRF) prevents myocardial injury in MI. However, the protective
mechanism at the metabolite level is unknown. Male Sprague-Dawley rats were
grouped into control, isoprenaline (ISO)-induced MI (MI), healthy rats
receiving 200 mg/kg TRF (200TRF), and MI rats receiving 200 mg/kg TRF
(200TRF+MI) groups. TRF was administered via oral gavage daily for 12 weeks
followed by intraperitoneal ISO injection (85 mg/kg) for two consecutive days
at a 24-hour interval to induce MI. High-performance liquid chromatography was
performed to analyze serum α-tocopherol and tocotrienol concentration
whereas ultra-high-performance liquid chromatography-mass spectrometry was used
for the untargeted metabolomic study. Serum α-tocopherol but not
tocotrienol was increased in the 200TRF (p=0.121) and 200TRF+MI (p<0.05)
following TRF supplementation. Multivariate analysis by Orthogonal Projections
to Latent Structures Discriminant Analysis showed high predictability of the
group comparison models for MI vs control and 200TRF+MI vs MI
(cross-validation: Q2>0.7, R2Y>0.8, p<0.05).
A total of 84 and 37 metabolites [when covariance of p≥|0.05|
(magnitude) and p(corr)≥|0.5| (reliability)] were significantly
different in the myocardial homogenates of MI vs control and 200TRF+MI vs MI,
respectively. MI rats had reduced S-adenosylmethionine and L-cystathionine that
might worsen MI by disturbing glutathione metabolism; decreased
phosphoribosyl-pyrophosphate and purine salvage process that might impair DNA
synthesis, and elevated glucose-6-phosphate suggesting enhanced anaerobic
glycolysis possibly for rapid production of energy. Conversely, TRF
supplementation reversed the impaired metabolic pathways caused by MI.
Keywords: Isoprenaline; liquid
chromatography-mass spectrometry; metabolomics; myocardial infarction;
tocotrienol-rich fraction
ABSTRAK
Dalam infarksi miokardium (MI),
penurunan tenaga, tekanan oksidatif, serta pengurangan metabolisme asid amino
mengubah metabolit dalam tisu. Bukti terkini menunjukkan bahawa fraksi kaya
tokotrienol (TRF) mencegah kecederaan miokardium dalam MI. Namun, mekanisme perlindungannya
pada tahap metabolit masih tidak diketahui. Tikus Sprague-Dawley jantan dibahagikan kepada kumpulan kawalan, MI aruhan isoprenalin (ISO) (MI),
tikus sihat yang menerima 200 mg/kg TRF (200TRF), dan tikus MI yang menerima
200 mg/kg TRF (200TRF+MI). TRF diberikan melalui gavaj oral setiap hari selama
12 minggu diikuti suntikan ISO secara intraperitoneum (85 mg/kg) dua hari
berturut-turut berselang 24 jam untuk mengaruh MI. Kromatografi cecair
berprestasi tinggi digunakan untuk menganalisis kepekatan serum
α-tokoferol dan tokotrienol manakala kromatografi cecair berprestasi
ultra-tinggi-spektrometri jisim digunakan untuk kajian metabolomik tanpa
sasaran. Serum α-tokoferol tetapi tidak tokotrienol telah meningkat bagi
kumpulan 200TRF (p=0.121) dan 200TRF+MI (p<0.05) setelah
disuplementasi TRF. Analisis multivariat oleh Unjuran Ortogon kepada Analisis Diskriminasi Struktur Pendam menunjukkan
kebolehramalan yang tinggi bagi model perbandingan antara kumpulan MI vs
kawalan dan 200TRF+MI vs MI (pengesahan silang: Q2>0.7, R2Y>0.8,
p<0.05). Sebanyak 84 dan 37 metabolit [apabila kovarians p≥|0.05|
(magnitud) dan p(corr)≥|0.5| (kebolehpercayaan)] berbeza secara
signifikan dalam homogenat miokardium masing-masing bagi kumpulan MI vs kawalan
dan 200TRF+MI vs MI. Tikus MI mengalami penurunan S-adenosilmetionina dan
L-sistationina yang mungkin meningkatkan keterukan MI melalui gangguan
metabolisme glutation; pengurangan fosforibosil-pirofosfat dan proses
penyelamatan purina yang mungkin menjejaskan sintesis DNA, serta peningkatan
glukosa-6-fosfat bagi proses glikolisis anaerob yang mungkin bertujuan
menghasilkan tenaga secara pantas. Sebaliknya, suplementasi TRF menghalang
penjejasan pada laluan metabolisma yang dicetuskan oleh MI.
Kata kunci: Fraksi kaya tokotrienol; infarksi miokardium; isoprenalin;
kromatografi cecair-spektrometri jisim; metabolomik
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*Pengarang untuk
surat-menyurat; email: zakiah.jubri@ppukm.ukm.edu.my
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