Cellular Respiration is Reduced in Ventricular Fibroblasts from Human Failing Heart under Statin Therapy
Authors: Ross Gracious , Emelyanova Larisa , Rizvi Farhan , Downey Frank X , Tajik Jamil , Jahangir Arshad 
Published: June 2021

Background

Cardiac fibrosis (CF) is a major factor underlying heart failure (HF) progression. HMG‐CoA (3‐hydroxy‐3‐methylglutaryl‐CoenzymeA) reductase inhibition by statins (indicated for dyslipidemia management) is reported to attenuate CF in various HF animal models but its effect in human failing heart ventricular fibroblasts (hVF), responsible for fibrosis, is not known. Also, statin‐induced mitochondrial inhibition in muscle is suggested to cause statin‐associated muscle disease, but its effect on hVF respiration is unknown. Hence, we compared the cellular respiration of hVF isolated from HF patients under statin therapy (HF+Statin) for at least 1 year to that not treated (HF‐No_Statin) and to hVFs from non‐failing hearts.

Methods

Primary cultures of hVFs from HF patients undergoing left‐ventricle assist device implantation either under‐ or no‐ statin therapy and from non‐diseased trauma victims (control) (n=6 each) were used at passage 3 or 4. After overnight culture in FM‐2 media at 25000 cells/well in collagen‐coated 96‐well Seahorse cell culture plate, cellular respiration was quantified using the Seahorse Extracellular Flux Analyzer XF‐96, as oxygen consumption rate (OCR) at baseline and following application of each well with mitochondrial modulators: Oligomycin (1μg/ml), FCCP (0.1μM) and antimycin A (1μg/ml), normalized to total protein, analyzed by unpaired t test or one‐Way Analysis of Variance.

Results

Basal or resting state respiration was significantly decreased (p=0.02) in hVFs from HF+statin group vs HF‐No_Statin, and control (0.14±0.06, 0.23±0.02 and 0.20±0.04 pmol O2/min/μg protein, respectively). Baseline respirations of hVFs from all three groups were suppressed by oligomycin, a specific inhibitor of mitochondrial ATP synthase and oxidative phosphorylation, however, was significantly reduced in HF+statin group compared to HF‐No_statin group. There was no significant difference in basal respiration between control and HF+No_statin groups (p=0.25). The maximal OCR of hVFs from control, HF‐No_Statin and HF+statin groups, determined after uncoupling of mitochondria with FCCP were 0.44±0.04, 0.52±0.06 and 0.26±0.10 pmol O2/min/μg protein, respectively. Non‐mitochondrial cellular OCR in hVFs, following treatment with antimycin A, a selective mitochondrial respiratory chain inhibitor, were 0.05±0.009, 0.06±0.0004 and 0.02±0.03 pmol O2/min/μg protein, respectively, control, HF‐No_Statin and HF+statin groups. In HF+statin group, the maximal OCR was significantly reduced compared to control (p=0.02) and HF+No statin (p=0.01). The maximal OCR (p=0.02) and the non‐mitochondrial OCR (p=0.03) were significantly higher in the HF+No_statin group compared to control hVFs, suggesting a compensatory O2 consumption in HF. Moreover, the extracellular acidification rate (ECAR), a pointer of glycolytic activity, did not significantly differ among the groups.

Conclusion

Statin therapy in human failing heart is associated with an energetic remodeling of ventricular fibroblasts with reduced mitochondrial respiration without any change in the glycolytic activity.

Support or Funding Information

Aurora Cardiovascular Surgical Research Award (CVSRA: 570‐5028) to G.R.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.