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The Exploration of Aldehyde Dehydrogenase 2 in the Cardioprotection of Fasudil

Author: YeHongWei
Tutor: WuJiFeng;GaoQin
School: Anhui Medical University,
Course: Pathology and Pathophysiology
Keywords: Ischemia/reperfusion injury Rho-kinase aldehyde dehydrogenase 2 cardioprotection fasudil cyanamide mitochondria
CLC: R54
Type: Master's thesis
Year: 2011
Downloads: 3
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Abstract


Objective: The cardiovascular disease has become the top killer that threat human life and health, the application of reperfusion therapy achieved good results, but it also brings a new problem--ischemia/reperfusion injury. So, clarifying the mechanism of ischemia/reperfusion injury, early resumption of perfusion while reducing reperfusion injury in clinical practice has become a new challenge.Rho/Rho kinase signaling pathway is involved in many major cardiovascular diseases such as hypertension, heart failure, myocardial infarction and atherosclerosis. The pathogenesis of myocardial ischemia/reperfusion injury relates to Rho/Rho kinase signaling pathway, it is reported that Rho-kinase inhibitor (fasudil) provides protective action on myocardial ischemia/reperfusion injury.Aldehyde dehydrogenase 2 (ALDH2) is an enzyme in mitochondria. Studies have shown that application of aldehyde dehydrogenase 2 agonists can protect the heart against ischemia/reperfusion injury. While the application of Rho-kinase inhibitors and activation of ALDH2 can both play cardioprotection against myocardial ischemia/reperfusion injury, however, whether they are related to each other remains unclear. In our study, the isolated heart perfusion system was used to mimic I/R injury model, Rho-kinase inhibitor fasudil and ALDH2 inhibitor cyanamide (CYA) were applied to observe the effects on heart, which want to clarify the relationship between fasudil’s myocardial protection and ALDH2, it can offer clues to the treatment for clinical ischemia/reperfusion injury.Methods: Male SD rats were randomly divided into four groups (n=8): (1) Ischemia/reperfusion injury group: Ligation left anterior descending coronary artery 30min in rats to simulate regional myocardial ischemia, then releasing the ligature to restore perfusion 120min as I/R; (2) Fasudil group: based on ischemia/reperfusion intervention, fasudil at 30umol/L was perfused from 10 min before ischemia until 10 min after reperfusion, totally perfusion for 50 min; (3) cyanamide (CYA) group: CYA at 1mmol/L was perfused from 10 min before ischemia until 10 min after reperfusion, totally perfusion for 50 min. (4) Fasudil+CYA group: fasudil at 30umol/L and CYA at 1mmol/L were both perfused in KH buffer from 10 min before ischemia until 10 min after reperfusion, totally perfusion for 50 min. In the experiment, the balloon was filled with water, then inserted into the left ventricle to maintain left ventricular end diastolic pressure (LVEDP) at 4-8 mmHg. Left ventricular developed pressure (LVDP), heart rate, maximal rise/fall rate of left ventricular pressure (±dp/dtmax) and LVEDP were continuous recorded, and rate pressure product (RPP=LVDP×HR) was calculated. The coronary effluent after myocardial reperfusion 5 min and 10 min was collected, and lactate dehydrogenase (LDH) levels in coronary effluent were determined. The samples were reserved at the end of reperfusion, the changes of ALDH2, Bcl-2 and Bax mRNA in myocardium were detected by reverse transcription polymerase chain reaction(PCR); some samples were observed with electron microscope.Result: (1) The changes of ventricular hemodynamic parameters: In I/R group, during ischemia and reperfusion period, compared with baseline, LVDP,±dp/dtmax, RPP were lower and LVEDP was higher; Compared with I/R group, fasudil decreased LVEDP, significantly increased the restore of LVDP and increased RPP; Compared with Fasudil group, CYA reduced the effect of fasudil’s myocardial protection, which reduced LVDP,±dp/dtmax and RPP.(2) Lactate dehydrogenase (LDH) level detection: Compared with I/R group, Fasudil significantly reduced LDH release, CYA significantly increased LDH release; and CYA attenuated the role of Fasudil.(3) RT-PCR detection of ALDH2, Bcl-2 and Bax mRNA: Compared with normal group, I/R group reduced the expression of ALDH2 mRNA and Bcl-2/Bax ratio in myocardial tissue, Bcl-2/Bax ratio decreased obviously in CYA group; Compared with I/R group, Fasudil increased the expression of ALDH2 mRNA and Bcl-2/Bax ratio, CYA reduced the expression of ALDH2 mRNA and Bcl-2/Bax ratio; in Fasudil+CYA group, the expression of ALDH2 mRNA and Bcl-2/Bax ratio was lower than Fasudil group.(4) Electron microscope detection: In normal group, myocardial myofibril and sarcomere arranged in neat mitochondria membrane was integrity and no swelling, mitochondrial cristae was clear and arranged regularly. In I/R group, myocardial myofibril arranged irregularly, sarcomere was fractured. Mitochondria were swelling, and mitochondrial membrane was not integrity, mitochondrial cristae were disappeared, cavitation bubble was formed; In Fasudil group, myocardial myofibril was arranged neatly, part of which was arranged fuzzy. Mitochondrial membrane was integrity, and part of mitochondrial cristae was arranged fuzzy; In Fasudil+CYA group, myocardial myofibril was irregular arrangement, sarcomere was fractured. Mitochondrial membrane was swelling and incomplete, mitochondrial cristae was ruptured and disappearance, there was cavitation bubble.Conclusions: Fasudil can play the myocardial protection against I/R injury, cyanamide, the inhibitor of ALDH2 can attenuated the protection of fasudil, which indicate that fasudil can increase the expression of ALDH2 to play the cardioprotective effect.

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