Abstract
Heart failure is the end-stage of all cardiovascular diseases with a ~25% 5-year survival rate, and insufficient mitochondrial energy production to meet myocardial demand is the hallmark of heart failure. Mitochondrial components involved in the regulation of ATP production remain to be fully elucidated. Recently, roles of 2′,3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) in the pathophysiological processes of heart diseases have emerged, implicated by evidence that mitochondrial CNPase proteins are associated with mitochondrial integrity under metabolic stress. In this study, a zebrafish heart failure model was established, by employing antisense morpholino oligonucleotides and the CRISPR-Cas9 gene-editing system, which recapitulates heart failure phenotypes including heart dysfunction, pericardial edema, ventricular enlargement, bradycardia, and premature death. The translational implications of CNPase in the pathophysiological process of heart failure were tested in a pressure overload-induced heart hypertrophy model, which was carried out in rats through transverse abdominal aorta constriction (TAAC). AAV9-mediated myocardial delivery of CNPase mitigated the hypertrophic response through the specific hydrolysis of 2′-3′-cyclic nucleotides, supported by the decrease of cardiac hypertrophy and fibrosis, the integrity of mitochondrial ultrastructure, and indicators of heart contractility in the AAV9-TAAC group. Finally, the biometrics of a mitochondrial respiration assay carried out on a Seahorse cellular energy analyzer demonstrated that CNPase protects mitochondrial respiration and ATP production from AngII-induced metabolic stress. In summary, this study provides mechanistic insights into CNPase-2′,3′-cyclic nucleotide metabolism that protects the heart from energy starvation and suggests novel therapeutic approaches to treat heart failure by targeting CNPase activity.
Highlights
We found that zebrafish larvae with morpholino-mediated cnpase silencing develop a heart failure phenotype, featuring increased ventricular size, impaired contractility and relaxation, edema, and cardiac arrhythmia
A zebrafish model with heart failure was developed using CRISPR-Cas9-mediated genetic manipulation. This animal model could be widely used to define the role of cyclic nucleotide-3 -phosphodiesterase (CNPase) in mitochondrial energy production during heart failure
AAV9-mediated delivery of CNPase provides mechanistic insights into CNPase-20,30 -cyclic nucleotide metabolism that protects the heart from energy starvation, and suggests novel therapeutic approaches to treat heart failure
Summary
Heart failure is the end-stage of cardiovascular disease and represents the top threat to public health worldwide. Despite accomplishments in therapeutics for heart failure, with a. 5-year mortality rate of 75%, the prognostic results are far from satisfactory [1]. Cardiac pathological hypertrophy usually precedes the onset of heart failure and is characterized by enlarged cardiomyocytes, thickening, and stiff ventricular walls due to pressure overload, mutations of sarcomeric proteins, or infarction-induced cardiomyocyte loss [2]. The deficiency of ATP production plays a central role in the pathogenesis and progression of heart failure phenotypes [3]. At present, improving myocardial energy homeostasis with neuroendocrine systems and heart rate management has emerged as a core strategy for treating heart failure [4]
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