Moderate exercise mitigates cardiac dysfunction and injury induced by cyclosporine A through activation of the PGI2 / PPAR-γ signaling pathway

Abstract

Background and purpose: The present study investigated the role of the prostaglandin I₂/peroxisome proliferator activator receptor (PGI2/PPAR) signaling pathway in cardiac cell proliferation, apoptosis, and systemic hemodynamic variables under cyclosporine A (CsA) exposure alone or combined with moderate exercises.

Experimental approach: Twenty-four male Wistar rats were classified into three groups, namely, control, CsA, and CsA + exercise.

Findings/results: After 42 days of treatment, the findings showed a significant enhancement in the expression of the β-MHC gene, enhancement in protein expression of Bax and caspase-3, and a significant decline in the protein expression of Bcl-2 expression, as well as increased proliferation intensity in the heart tissue of the CsA group compared to the control group. Systolic pressure, pulse pressure, mean arterial pressure (MAP), QT and QRS duration, and T wave amplitude, as well as QTc amount in the CsA group, showed a significant increase compared to the control group. PPAR-γ and PGI₂ showed no significant changes compared to the control group. Moderate exercise along with CsA significantly enhanced the protein expression of PPAR-γ and PGI2 and declined protein expression of Bax, and caspase-3 compared to those in the CsA group. In the CsA + exercise group, systolic pressure, MAP, and T_wave showed a significant decrease compared to the CsA group. Moderate exercises along CsA improved heart cell proliferation intensity and significantly reduced β- MHC gene expression compared to the CsA group.

Conclusions and implications: The results showed moderate exercise alleviated CsA-induced heart tissue apoptosis and proliferation with the corresponding activation of the PGI₂/PPAR-γ pathway.

Keywords: Cyclosporine; Exercise; Heart; PGI2/PPAR signaling pathway; Proliferation.

Fig. 1

The effect of chronic administration of CsA (30 mg/kg/day for 6 weeks, gavage) and CsA along with moderate exercise on the HR, SBP, DBP, MAP, PP, and DP in male rats (n = 8). Systemic hemodynamic variables were determined by the digital waveform contour analyzing method directly recording from the carotid artery. Data are given as mean ± SEM. ^*P < 0.05 Indicates significant differences compared to the control and ^#P < 0.05 versus the CsA group. CsA, Cyclosporine A; Exe, exercise; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; PP, pulse pressure; DP, dicrotic pressure.

Fig. 2

Comparisons of electrocardiogram parameters including (A) T wave, (B) OTc, and (C) QRS and QT between the CsA administration group (30 mg/kg/day for 6 weeks, gavage) and CsA along with moderate exercise group in the male rats (n = 8). Data are presented as mean ± SEM. ^*P < 0.05 and ^**P < 0.01 indicates significant differences compared to the control and ^#P < 0.05 versus the CsA group. CsA, Cyclosporine A; Exe, exercise.

Fig. 3

The influence of CsA exposure and CsA along with moderate exercise on the protein levels of Bax, Bcl-2, Bax/Bcl-2 ratio, and caspase-3 in the male rats' heart tissue. CsA induced apoptosis in rats cardiomyocytes. The expression of Bax, Bcl-2, and cleaved caspase-3 was examined by western blot. Data are presented as mean ± SEM. ^**P < 0.01 Indicates significant differences compared to the control and ^#P < 0.05 and ^##P < 0.01 versus the CsA group. CsA, Cyclosporine A; Exe, exercise.

Fig. 4

The influence of CsA administration and CsA along with moderate exercise on the PGI₂ and PPAR-γ protein expression levels, detected by western blot, in the heart tissue of male rats (n = 8). Data are expressed as mean ± SEM. ^*P < 0.05 and ^**P < 0.01 indicate significant differences compared to the control and ^#P < 0.05 and ^##P < 0.01 versus the CsA group. CsA, Cyclosporine A; Exe, exercise; PGI₂, prostaglandin I₂; PPAR-γ, peroxisome proliferator activator receptor.

Fig. 5

Effect of CsA administration and CsA along with moderate exercise on the mRNA expression levels of MHC isoforms and MHC-β/MHC-α ratio, quantified using real-time-polymerase chain reaction, in the heart tissue of male rats (n = 8). Data represent mean ± SEM. ^**P < 0.01 Indicates significant differences compared to the control and ^##P < 0.01 and ^###P < 0.001 versus the CsA group. CsA, Cyclosporine A; Exe, exercise; MHC, myosin heavy chain.

Fig. 6

(A) Immunohistochemical staining of PCNA in a section of male rats' cardiac tissues. An up-regulated expression of PCNA protein was represented with increased PCNA⁺ cells (arrowhead) versus PCNA^- (arrows) in the section from the cyclosporine group (25 μm). A significant reduction in the PCNA expression in the CsA + Exe group compared to the cyclosporine group (25 μm) and (B) pixel-based intensity analysis for brown reaction (representing PCNA) in 1270 μm × 1270 μm of tissue in different groups, (C) mean percentages of PCNA+ cells per 1 mm² of tissue in different groups; data are presented as mean} SEM. ^**P < 0.01 and ^***P < 0.001 indicates significant differences compared to the control and ^##P < 0.01 versus the CsA group. CsA, Cyclosporine A; Exe, exercise; PCNA, anti-proliferating cell nuclear antibody.