Mitochondrial integrity in a neonatal bovine model of right ventricular dysfunction

Abstract

(LV) failure, yet the mechanisms of RV failure are poorly understood. Recent studies suggest cardiac metabolism is altered in RV failure in pulmonary hypertension (PH). Accordingly, we assessed mitochondrial content, dynamics, and function in hearts from neonatal calves exposed to hypobaric hypoxia (HH). This model develops severe PH with concomitant RV hypertrophy, dilation, and dysfunction. After 2 wk of HH, pieces of RV and LV were obtained along with samples from age-matched controls. Comparison with control assesses the effect of hypoxia, whereas comparison between the LV and RV in HH assesses the additional impact of RV overload. Mitochondrial DNA was unchanged in HH, as was mitochondrial content as assessed by electron microscopy. Immunoblotting for electron transport chain subunits revealed a small increase in mitochondrial content in HH in both ventricles. Mitochondrial dynamics were largely unchanged. Activity of individual respiratory chain complexes was reduced (complex I) or unchanged (complex V) in HH. Key enzymes in the glycolysis pathway were upregulated in both HH ventricles, alongside upregulation of hypoxia-inducible factor-1␣ protein. Importantly, none of the changes in expression or activity were different between ventricles, suggesting the changes are in response to HH and not RV overload. Upregulation of glycolytic modulators without chamber-specific mitochondrial dysfunction suggests that mitochondrial capacity and activity are maintained at the onset of PH, and the early RV dysfunction in this model results from mechanisms independent of the mitochondria. pulmonary hypertension; right ventricle; cardiac; mitochondria HEART FAILURE (HF) is characterized by an inability of the ventricles to pump sufficient blood flow to working tissue. Regardless of upstream signaling, the failing heart cannot generate sufficient myofilament force to sustain adequate perfusion pressures. Multiple hypotheses have been put forward to explain this contractile deficit, including myofilament protein dysfunction. However, we have shown in a large animal model of right ventricular (RV) dysfunction that myofilament protein properties are not likely to be solely responsible for the contractile deficit, since isolated skinned cardiac myocytes from hypobaric hypoxia (HH) calves produce similar forces as skinned myocytes from control calves, despite significant organ-level dysfunction (42). Therefore, additional mechanisms must explain the contractile dysfunction observed. Myofilament contraction requires a reliable energy source in the form of ATP for generation of force and maintenance of intracellular calcium gradients. Cardiac hypertrophy and HF are associated with metabolic dysregulation and chronic energy deficiency (15, 29), suggesting energy deficits in the failing heart are associated with and may contribute to the contractile dysfunction. Although a number of metabolic changes have been examined, the outcomes in a number of animal models of ventricular failure have been discordant, with some models showing...

Differential Bioenergetics in Adult Rat Cardiomyocytes Isolated From the Right Versus Left Ventricle

“…[43][44][45][46] In bovine RV compared to LV, Bruns et al reported higher mitochondrial content by DNA copy number and morphometric analysis, as well as increased expression of pro-fusion Mfn1 mRNA, implicating enhanced mitochondrial fusion in the RV. 7,8 Our finding of increased Mfn1 protein expression and increased mtDNA levels in RV compared to LV myocytes similarly support increased mitochondrial fusion and content in RV myocytes, which can potentially underlie their enhanced maximal respiratory capacity. Although we did not directly assess cardiomyocyte ATP production, we observed increased complex V enzyme activity in RV myocytes, in line with the enhanced energetics associated with mitochondrial fusion.…”

“…29 Bruns et al showed in control calves increased RV versus LV mitochondrial content and expression of COXI (mitochondrial complex IV) and Mfn1, which regulates mitochondrial fusion. 7,8 Taken together, these studies suggest a mitochondrial basis for ventricular differences in metabolism.…”

“…1- 6 Accumulating evidence suggests that the mechanisms that underlie RV failure may diverge from those that occur in failure of the left ventricle (LV), thus underscoring the need for dedicated study of the RV. [7][8][9][10] Experimentally, the RV tolerates acute pressure overload more poorly compared to the LV. 11 Clinically, the time course to RV failure appears contracted compared to LV failure.…”

Update on novel targets and potential treatment avenues in pulmonary hypertension

“…Interestingly, all differences noted in the RV were also observed in the LV, suggesting an overall response to hypoxia rather than chamber-specific adaptation. A small shift in metabolism consistent with an early switch to glycolytic metabolism was also noted, although again this was observed in both ventricles (30), suggesting that at this early stage of PH where RV function is largely compensated, mitochondrial and metabolic pathways do not contribute to the response to pressure overload.…”

“…Consistent with previous work demonstrating metabolic dysregulation in the left ventricle (LV) during heart failure (19,204,215), it was speculated that similar mitochondrial and metabolic abnormalities might be present in the RV. Surprisingly, following 2 wk of hypoxic exposure, mitochondrial function appeared to be largely maintained, with no significant changes in mitochondrial structure or dynamics and only small reductions in mitochondrial number and complex I activity (30). Interestingly, all differences noted in the RV were also observed in the LV, suggesting an overall response to hypoxia rather than chamber-specific adaptation.…”