Metoprolol and bisoprolol ameliorate hypertrophy of neonatal rat cardiomyocytes induced by high glucose via the PKC/NF‑κB/c‑fos signaling pathway

Abstract

Hyperglycemia caused by diabetes mellitus could increase the risk of diabetic cardiomyopathy. However, to the best of our knowledge, the underlying mechanism of this process is still not fully explored. Thus, developing ways to prevent hyperglycemia can be beneficial for diabetic patients. The present study was designed to investigate the influence of metoprolol and bisoprolol on the cardiomyocytic hypertrophy of neonatal rat cardiomyocytes. Cardiomyocytes were cultured in two types of media: One with low glucose levels and one with high glucose levels. Cardiomyocytes cultured in high glucose were further treated with the following: A protein kinase C (PKC) inhibitor, an NF-κB inhibitor, metoprolol or bisoprolol. The pulsatile frequency, cellular diameter and surface area of cardiomyocytes were measured. Protein content and [ 3 H]-leucine incorporation were determined, atrial natriuretic peptide (ANP), α-myosin heavy chain (α-MHC) and β-myosin heavy chain (β-MHC) mRNA levels were calculated by reverse transcription-quantitative PCR, while the expression and activation of PKC-α, PKC-β 2 , NF-κB, tumor necrosis factor-α (TNF-α), and c-fos were detected by western blotting. Metoprolol or bisoprolol were also used in combination with PKC inhibitor or NF-κB inhibitor to determine whether the hypertrophic response would be attenuated to a lower extent compared with metroprolol or bisoprolol alone. Cardiomyocytes cultured in high glucose presented increased pulsatile frequency, cellular diameter, surface area, and protein content and synthesis, higher expression of ANP and β-MHC, and lower α-MHC expression. High glucose levels also upregulated the expression and activation of PKC-α, PKC-β 2 , NF-κB, TNF-α and c-fos. Metoprolol and bisoprolol partly reversed the above changes, while combined use of metoprolol or bisoprolol with PKC inhibitor or NF-κB inhibitor further ameliorated the hypertrophic response mentioned above to lower levels compared with using metroprolol or bisoprolol alone. In conclusion, metoprolol and bisoprolol could prevent hypertrophy of cardiomyocytes cultured in high glucose by the inhibition of the total and phospho-PKC-α, which could further influence the PKC-α/NF-κB/c-fos signaling pathway.

Inhibition of protein kinase C alpha attenuates lipopolysaccharide-triggered acute lung injury by alleviating the hyperinflammatory response and oxidative stress

“…Furthermore, PKCα is known to be upstream of NF-κB signaling. For example, Wang et al found that the PKCα/NF-κB/c-fos signaling pathway was critical for the development of diabetic cardiomyopathy-related cardiac hypertrophy (20). Other studies showed that high glucose levels promote the activation of PKCα, which can trigger NF-κB signaling, resulting in inflammation and lipid metabolism disorder in rat models of diabetes (11,21).…”

Protein kinases in cardiovascular diseases

“…In the model of cardiac hypertrophy, mibefradil, rapamycin, and aliskiren are found to inhibit PI3K/Akt/mTOR-mediated autophagy to alleviate CM hypertrophy and reverse cardiac remodeling [31–33] . Similarly, metoprolol and bisoprolol inhibit PKC to reverse cardiac hypertrophy [34] …”

Metoprolol Protects Against Arginine Vasopressin-Induced Cellular Senescence in H9C2 Cardiomyocytes by Regulating the Sirt1/p53/p21 Axis

“…With this anti-hypertensive property, it can also counterbalance an increase of the peripheral vascular resistance mainly dependent on the sympathetic innervation of small arterial myocytes [20]. Recently, Metoprolol showed significant protective effects on injured cardiomyocytes [21][22][23][24]. In the present study, we investigated the protective effect of Metoprolol against arginine vasopressininduced cell senescence to explore its potential therapeutic property of Metoprolol on pathological cardiac hypertrophy.…”