Abstract
Heart failure (HF) is a complex clinical syndrome with poor clinical outcomes despite the growing number of therapeutic approaches. It is characterized by interstitial fibrosis, cardiomyocyte hypertrophy, activation of various intracellular signalling pathways, and damage of the mitochondrial network. Mitochondria are responsible for supplying the energy demand of cardiomyocytes; therefore, the damage of the mitochondrial network causes cellular dysfunction and finally leads to cell death. BGP-15, a hydroxylamine derivative, is an insulin-sensitizer molecule and has a wide range of cytoprotective effects in animal as well as in human studies. Our recent work was aimed at examining the effects of BGP-15 in a chronic hypertension-induced heart failure model. 15-month-old male SHRs were used in our experiment. The SHR-Baseline group represented the starting point (n = 7). Animals received BGP-15 (SHR-B, n = 7) or placebo (SHR-C, n = 7) for 18 weeks. WKY rats were used as age-matched normotensive controls (n = 7). The heart function was monitored by echocardiography. Histological preparations were made from cardiac tissue. The levels of signalling proteins were determined by Western blot. At the end of the study, systolic and diastolic cardiac function was preserved in the BGP-treated animals. BGP-15 decreased the interstitial collagen deposition via decreasing the activity of TGFβ/Smad signalling factors and prevented the cardiomyocyte hypertrophy in hypertensive animals. BGP-15 enhanced the prosurvival signalling pathways (Akt/Gsk3β). The treatment increased the activity of MKP1 and decreased the activity of p38 and JNK signalling routes. The mitochondrial mass of cardiomyocytes was also increased in BGP-15-treated SHR animals due to the activation of mitochondrial biogenesis. The mitigation of remodelling processes and the preserved systolic cardiac function in hypertension-induced heart failure can be a result—at least partly—of the enhanced mitochondrial biogenesis caused by BGP-15.
Highlights
Heart failure remained a leading cause of death despite the broadening of therapeutic possibilities [1]
At the end of the study, the heart weights (HW) and ventricles weight (VW) were significantly increased in the Spontaneously hypertensive rat (SHR) groups compared to the Wistar Kyoto (WKY) group (HW: WKY: 1:12 ± 0:04 g, SHR-Baseline: 1:16 ± 0:02, SHR-C: 1:49 ± 0:05 g, SHR-B: 1:23 ± 0:02 g; p < 0:01 SHR-B and SHR-C vs. WKY; VW: WKY: 0:95 ± 0:04 g, SHR-Baseline: 1:09 ± 0:02 g, SHR-C: 1:33 ± 0:05 g, SHR-B: 1:23 ± 0:02 g; p < 0:01 SHRC vs. WKY, p < 0:01 SHR-B vs. SHR-C)
The ratio of ventricular weight to body weight (VW/BW) was increased markedly in the SHR groups compared to WKY animals (VW/BW(mg/g): WKY: 2:28 ± 0:11, SHR-Baseline: 3:19 ± 0:08, SHR-C: 3:73 ± 0:16, SHR-B: 3:21 ± 0:03; p < 0:01 SHR groups vs. WKY, p < 0:05 SHR-B vs. WKY, p < 0:01 WKY vs. SHR-Baseline and SHR-C, p < 0:01 SHR-C vs. SHR-Baseline, p < 0:01 SHR-B vs. SHR-C)
Summary
Heart failure remained a leading cause of death despite the broadening of therapeutic possibilities [1]. The most important risk factors of heart failure are ischemic heart disease and hypertension [2]. The treatment of hypertension is challenging; there is a high portion of patients who cannot reach the goal blood pressure level having a high risk for the development of heart failure [3]. Sustained elevation of blood pressure induces myocardial remodelling, which is characterized by interstitial fibrosis and cardiomyocyte hypertrophy [4, 5]. These cellular alterations are promoted by oxidative stress [6] and by the activation of various intracellular signal transduction pathways [7, 8].
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