Diabetic cardiomyopathy (DCM) is one of the major causes of morbidity and mortality in diabetic patients. Recent studies have demonstrated an increased level of fibroblast growth factor 21 (FGF21) in the plasma of DCM patients, and FGF21 has been proven to be a cardiovascular protector of the heart. The present study aimed to further investigate the pathogenic role of FGF21 in DCM, hypothesizing that a lack of FGF21 may promote the progression of DCM by regulating the lipid metabolism, cardiac hypertrophy and cardiac fibrosis, thus deteriorating the cardiac dysfunction. A total of 44 mice were randomly assigned into the normal (n=6), DCM (n=6), normal + scrambled siRNA (n=6), DCM + scrambled siRNA (n=6), normal + FGF21 siRNA (n=10) and DCM + FGF21 siRNA (n=10) groups. Type 1 diabetes mellitus was induced to mice in the DCM groups by streptozotocin injection, while FGF21 expression was inhibited by FGF21 siRNA. Normal and DCM mice administrated with scrambled siRNA were respectively regarded as the controls for the normal + FGF21 siRNA and DCM + FGF21 siRNA groups. In the DCM group, FGF21 inhibition promoted cardiac hypertrophy and fibrosis, and the expression levels of their indicators, including atrial natriuretic factor, α-skeletal actin, collagen type I and III, and transforming growth factor-β, increased, leading to further decreased cardiac function. In addition, FGF21 inhibition in DCM mice elevated the quantity of lipid droplets and the concentration of heart triglycerides, plasma triglycerides and cholesterol levels, accompanied by downregulation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and upregulation of cluster of differentiation (CD)36. Thus, the results indicated that FGF21 inhibition exacerbates the cardiac dysfunction by aggravating the lipid accumulation through regulating the expression levels of PGC-1α and CD36. In conclusion, it is suggested that FGF21 may be a potentially useful agent in the treatment of DCM.

The underlying mechanism of cardiac hypertrophy has not yet been fully elucidated. The present study aimed to explore the function of transcription factor EC (TFEC) in mouse models of cardiac hypertrophy and to determine the underlying mechanism. Pressure-overload cardiac hypertrophy and angiotensin II (AngII) infusion-induced animal models of cardiac hypertrophy were established in vivo. The expression of TFEC was explored via western blotting. The results demonstrated that TFEC expression was significantly increased in the hearts of mice with pressure overload- and AngII-induced hypertrophy. Injection of rAd-short hairpin (sh)-TFEC significantly decreased the expression of TFEC in heart tissues compared with group injected with rAd-negative control (NC). Furthermore, the expression levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) were increased in the hearts of AngII-treated mice; however, compared with rAd-NC transfection, transfection with rAd-sh-TFEC decreased the expression levels of ANP, BNP and β-MHC. The results from echocardiographic analysis indicated that transfection with rAd-sh-TFEC improved the cardiac function of AngII-treated mice compared with transfection with rAd-NC. In addition, the AngII-induced increase in cardiomyocyte size could be reversed by TFEC knockdown in primary cardiomyocytes. The elevated expression levels of ANP, BNP and β-MHC induced by AngII could be partially abolished following TFEC knockdown. The results from western blotting demonstrated that TFEC overexpression decreased the expression of phosphorylated AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) but increased the expression of phosphorylated mechanistic target of rapamycin (mTOR). Furthermore, Compound C significantly suppressed the activation of AMPK/ACC but increased the activation of mTOR, even in primary cardiomyocytes transfected with rAd-sh-TFEC. In conclusion, the findings from this study demonstrated that TFEC was overexpressed in the hearts of mice with cardiac hypertrophy and that silencing TFEC may improve AngII-induced cardiac hypertrophy and dysfunction by activating AMPK/mTOR signaling.

Pathological cardiac hypertrophy induced by aging and neurohumoral activation, such as angiotensin II (Ang II) activation, is an independent risk factor for heart failure. The muscle really interesting new gene-finger protein-1 (MuRF1) and muscle atrophy F-box (MAFbx) pathway has been previously reported to be an important mechanism underlying the pathogenesis of cardiac hypertrophy. Metformin is currently the first-line blood glucose-lowering agent that can be useful for the treatment of cardiovascular diseases. However, the potential role of metformin in the modulation of MuRF1 and MAFbx in cardiomyocyte hypertrophy remains poorly understood. The present study used H9c2 cells, a cardiomyocyte cell model. The surface area of cultured rat H9c2 myoblasts was measured and the expression levels of MuRF1 and MAFbx were quantified using western blot or reverse transcription-quantitative PCR. H9c2 cells were transfected with MuRF1 and MAFbx small interfering (si) RNA. The present study revealed that Ang II treatment significantly increased the cell surface area of model cardiomyocytes. Additionally, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNA and protein expression was increased following this treatment. Ang II also downregulated MuRF1 and MAFbx protein and mRNA expression. In the H9C2, treatment with metformin attenuated hypertrophic remodeling. In addition, expression of ANP and BNP was significantly reduced in metformin-treated H9C2 cells. The results indicated that metformin increased the activity of MuRF1 and MAFbx and upregulated their expression, the knockdown of which resulted in deteriorative Ang II-induced cell hypertrophy, even following treatment with metformin. Taken together, data from the present study suggest that metformin can prevent cardiac hypertrophy through the MuRF1 and MAFbx pathways.

Cardiac hypertrophy is one of the key structural changes that occurs in diabetic cardiomyopathy. Previous studies have indicated that the activation of NF-κB by calpain-1, a Ca2+-dependent cysteine protease, serves an important role in cardiac hypertrophy. The aim of the present study was to assess the effect of 30 and 60 mg/kg Lycium barbarum polysaccharide (LBP) treatment, the major active ingredient extracted from Lycium barbarum, on cardiac hypertrophy in streptozotocin (STZ) induced diabetic rats. In addition, the present study examined the possible underlying mechanisms of this effect by assessing calpain-1 expression and the NF-κB pathway. The mRNA expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was determined by reverse transcription-quantitative PCR. Western blotting was used to detect the protein expressions of calpain-1, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and toll-like receptor-4 (TLR-4) in the heart tissue. The results revealed that compared with non-diabetic rats, diabetic rats exhibited cardiac hypertrophy. Cardiac hypertrophy was defined by the following: Dysfunction of the cardiac hemodynamics, an increase in the ratios of left ventricular weight/body weight and heart weight/body weight and the increased expressions of ANP and BNP, which serve as hypertrophic markers in cardiac tissue. However, all of these changes were attenuated in diabetic rats treated with LBP. In addition, the protein expression of calpain-1 was increased in the heart tissue of diabetic rats compared with that of non-diabetic rats, where it was inhibited by LBP. LBP also decreased the protein expression of certain inflammatory mediators, IL-6, TNF-α, ICAM-1, VCAM-1 and TLR-4 in diabetic heart tissue. Furthermore, LBP treatment reduced the production of reactive oxygen species, upregulated the protein expression of endothelial nitric oxide synthase and downregulated the protein expression of inducible nitric-oxide synthase. Additionally, LBP increased the protein expression of p65, the subunit of NF-κB and inhibitory protein кB-α in the cytoplasm and reduced p65 expression in the nucleus. In conclusion, LBP improves cardiac hypertrophy, inhibits the expression of calpain-1 and inhibits the activation of NF-κB in diabetic rats.

Myocardial hypertrophy is an independent risk factor of cardiovascular diseases and is closely associated with the incidence of heart failure. In the present study, we hypothesized that difluoromethylornithine (DFMO) could attenuate cardiac hypertrophy through mitochondria-associated membranes (MAM) and autophagy. Cardiac hypertrophy was induced in male rats by intravenous administration of isoproterenol (ISO; 5 mg/kg/day) for 1, 3,7 and 14 days. For DFMO treatment group, rats were given ISO (5 mg/kg/day) for 14 days and 2% DFMO in their water for 4 weeks. The expression of atrial natriuretic peptide (ANP) mRNA,heart parameters, apoptosis rate, fibrotic area and protein expressions of cleaved caspase3/9, GRP75, Mfn2, CypD and VDAC1 were measured to confirm the development of cardiac hypertrophy, apoptosis and autophagy induced by ISO. ANP mRNA and MAM protein expression levels were assessed by reverse transcription-quantitative PCR and western blotting to evaluate hypertrophy and the effects of DFMO oral administration. The results demonstrated that heart parameters, ANP mRNA levels, fibrotic area and apoptosis rate were significantly increased in the heart tissue for ISO 7 and 14 day groups compared with the control group. Furthermore, treatment with DFMO significantly inhibited these indicators, and DFMO downregulated the MAM signaling pathway and upregulated the autophagy pathway in heart tissue compared with the ISO 14 day group. Overall, all ISO-induced changes analyzed in the present study were attenuated following treatment with DFMO. The findings form this study suggested that DFMO treatment may be considered as a potential strategy for preventing ISO-induced cardiac hypertrophy.

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 [3H]-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-β2, 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-β2, 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.