BGP‐15 Protects against Heart Failure by Enhanced Mitochondrial Biogenesis and Decreased Fibrotic Remodelling in Spontaneously Hypertensive Rats

Figures

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  Figure 1. Effect of BGP-15 treatment on the extent of interstitial fibrosis, collagen type I deposition, and on the diameter of cardiomyocytes. Representative histological sections stained with Picrosirius red (a) (n = 7). Scale bar: 150 μm, magnification: 10-fold. Densitometric evaluation of the sections is shown (b). ∗p < 0.05 vs. WKY, ∗∗p < 0.01 vs. WKY, ##p < 0.01 vs. SHR-Baseline, §§p < 0.01 vs. SHR-C. Representative histological sections detected with collagen type I immunohistochemistry (c) (n = 7). Scale bar: 100 μm, magnification: 10-fold. Densitometric evaluation of the sections is shown (d). ∗∗p < 0.01 vs. WKY, ##p < 0.01 vs. SHR-C, §§p < 0.01 vs. SHR-C. Representative histological sections stained with Picrosirius red (e) (n = 7). Scale bar: 50 μm, magnification: 10-fold. The average cellular diameter in the different groups is shown (f). ∗∗p < 0.01 vs. WKY, #p < 0.05 vs. SHR-Baseline, §§p < 0.01 vs. SHR-C. WKY: age-matched normotensive Wistar-Kyoto rats; SHR-Baseline: 15-month-old spontaneously hypertensive rats; SHR-C: 19-month-old spontaneously hypertensive rats received placebo for 18 weeks; SHR-B: 19-month-old spontaneously hypertensive rats received BGP-15 for 18 weeks.

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  Figure 2. Effect of BGP-15 treatment on the TGFβ/Smad signalling pathway. Representative Western blot analysis of TGFβ, Smad2, Smad3, and phosphorylation and densitometric evaluation are shown. GAPDH was used as a loading control. WKY: age-matched normotensive Wistar-Kyoto rats, n = 7; SHR-Baseline: 15-month-old spontaneously hypertensive rats, n = 7; SHR-C: nontreated spontaneously hypertensive rats, n = 7; SHR-B: spontaneously hypertensive rats receiving BGP-15 for 18 weeks, n = 7. Values are mean ± SEM. ∗p < 0.05 vs. WKY, ∗∗p < 0.01 vs. WKY, #p < 0.05 vs. SHR-Baseline, §§p < 0.01 vs. SHR-C.

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  Figure 3. Effect of BGP-15 treatment on the phosphorylation of Akt-1Ser473 and GSK-3βSer9. Representative Western blot analysis of Akt-1 and GSK-3β phosphorylation and densitometric evaluation are shown. GAPDH was used as a loading control. WKY: age-matched normotensive Wistar-Kyoto rats, n = 7; SHR-Baseline: 15-month-old spontaneously hypertensive rats, n = 7; SHR-C: nontreated spontaneously hypertensive rats, n = 7; SHR-B: spontaneously hypertensive rats receiving BGP-15 for 18 weeks, n = 7. Values are mean ± SEM. ∗∗p < 0.01 vs. WKY, ##p < 0.01 vs. SHR-Baseline, §p < 0.05 vs. SHR-C, §§p < 0.01 vs. SHR-C.

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  Figure 4. Effect of the BGP-15 treatment on the phosphorylation state of MAP kinases and on MKP-1. Representative Western blot analysis of MKP-1 as well as ERK1/2, p38, and JNK phosphorylation. Densitometric evaluation is also shown. GAPDH was used as a loading control. WKY: age-matched normotensive Wistar-Kyoto rats, n = 7; SHR-Baseline: 15-month-old spontaneously hypertensive rats, n = 7; SHR-C: nontreated spontaneously hypertensive rats, n = 7; SHR-B: spontaneously hypertensive rats receiving BGP-15 for 18 weeks, n = 7. Values are mean ± SEM. ∗p < 0.05 vs. WKY, ∗∗p < 0.01 vs. WKY, ##p < 0.01 vs. SHR-Baseline, §§p < 0.01 vs. SHR-C.

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  Figure 5. Effect of the BGP-15 treatment on the regulation of mitochondrial biogenesis. Representative Western blot analysis of PGC-1α, VDAC, CREB, AMPK, and phosphorylation of CREB and AMPK. Densitometric evaluation is also shown. GAPDH was used as a loading control. WKY: age-matched normotensive Wistar-Kyoto rats, n = 7; SHR-Baseline: 15-month-old spontaneously hypertensive rats, n = 7; SHR-C: nontreated spontaneously hypertensive rats, n = 7; SHR-B: spontaneously hypertensive rats receiving BGP-15 for 18 weeks, n = 7. Values are mean ± SEM. ∗p < 0.05 vs. WKY, ∗∗p < 0.01 vs. WKY, ##p < 0.01 vs. SHR-Baseline, §p < 0.05 vs. SHR-C, §§p < 0.01 vs. SHR-C.

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  Figure 6. The suspected mechanism of BGP-15 treatment in a hypertension-induced heart failure model. BGP-15 has a beneficial effect against hypertension-induced cardiac remodelling and cardiac fibrosis. The BGP-15 treatment decreases the activity of TGFβ/Smad and MAPK signalling factors and in this way prevents against hypertension-induced interstitial collagen deposition. BGP-15 favourably influences the prosurvival signalling pathways. Moreover, the mitochondrial biogenesis is activated due to BGP-15 administration, thereby resulting in an increase in mitochondrial mass.