Korean Circ J.  2018 Dec;48(12):1135-1144. 10.4070/kcj.2018.0061.

Protective Effect of Right Ventricular Mitochondrial Damage by Cyclosporine A in Monocrotaline-induced Pulmonary Hypertension

• Lee DS
• Jung YW

• KMID: 2424563
• DOI: http://doi.org/10.4070/kcj.2018.0061

Abstract

BACKGROUND AND OBJECTIVES
Mitochondria play a key role in the pathophysiology of heart failure and mitochondrial permeability transition pore (MPTP) play a critical role in cell death and a critical target for cardioprotection. The aim of this study was to evaluate the protective effects of cyclosporine A (CsA), one of MPTP blockers, and morphological changes of mitochondria and MPTP related proteins in monocrotaline (MCT) induced pulmonary arterial hypertension (PAH).
METHODS
Eight weeks old Sprague-Dawley rats were randomized to control, MCT (60 mg/kg) and MCT plus CsA (10 mg/kg/day) treatment groups. Four weeks later, right ventricular hypertrophy (RVH) and morphological changes of right ventricle (RV) were done. Western blot and reverse transcription polymerase chain reaction (RT-PCR) for MPTP related protein were performed.
RESULTS
In electron microscopy, CsA treatment prevented MCT-induced mitochondrial disruption of RV. RVH was significantly increased in MCT group compared to that of the controls but RVH was more increased with CsA treatment. Thickened medial wall thickness of pulmonary arteriole in PAH was not changed after CsA treatment. In western blot, caspase-3 was significantly increased in MCT group, and was attenuated in CsA treatment. There were no significant differences in voltage-dependent anion channel, adenine nucleotide translocator 1 and cyclophilin D expression in western blot and RT-PCR between the 3 groups.
CONCLUSIONS
CsA reduces MCT induced RV mitochondrial damage. Although, MPTP blocking does not reverse pulmonary pathology, it may reduce RV dysfunction in PAH. The results suggest that it could serve as an adjunctive therapy to PAH treatment.

Keyword

Pulmonary circulation; Pulmonary hypertension; Heart ventricles; Mitochondria

MeSH Terms

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Adenine Nucleotide Translocator 1
Arterioles
Blotting, Western
Caspase 3
Cell Death
Cyclophilins
Cyclosporine*
Heart Failure
Heart Ventricles
Hypertension
Hypertension, Pulmonary*
Hypertrophy, Right Ventricular
Microscopy, Electron
Mitochondria
Monocrotaline
Pathology
Permeability
Polymerase Chain Reaction
Pulmonary Circulation
Rats, Sprague-Dawley
Reverse Transcription
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Adenine Nucleotide Translocator 1
Caspase 3
Cyclophilins
Cyclosporine
Monocrotaline

Figure

• 

  Figure 1 TEM findings. The ultrastructure of the mitochondria in MCT group were swollen, disrupted, and disorganized. CsA treatment prevented mitochondrial damage dramatically (×10,000–20,000). CsA = cyclosporine A; NC = normal control; MCT = monocrotaline; NC = normal control; TEM = transmission electron microscopy.

• 

  Figure 2 Western blot. There were no significant changes in VDAC, ANT1, CypD, and AIF expression (A-C and E). Casp3 was significantly increased in MCT group, but was significantly attenuated in CsA treatment (D). Values are presented as mean±SD. AIF = apoptosis-inducing factor; ANT1 = adenine nucleotide translocator 1; Casp3 = caspase-3; CsA = cyclosporine A; CypD = cyclophilin D; MCT = monocrotaline; NC = normal control; SD = standard deviation; VDAC = voltage-dependent anion channel. *p<0.05 vs. NC group; †p<0.05 vs. MCT group.

• 

  Figure 3 RT-PCR. The expression of VDAC, ANT1, and CypD was not significantly changed in all 3 groups (A-C). Values are presented as mean±SD. ANT1 = adenine nucleotide translocator 1; CypD = cyclophilin D; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; MCT = monocrotaline; NC = normal control; RT-PCR = reverse transcription polymerase chain reaction; SD = standard deviation; VDAC = voltage-dependent anion channel.

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