Inhibition of prolyl hydroxylases alters cell metabolism and reverses pre-existing diastolic dysfunction in mice
Introduction
Diastolic dysfunction is one of the major characteristics of heart failure with preserved ejection fraction (HFpEF), as well as in some population of asymptomatic patients and patients with reduced EF (HFrEF) [1]. More than half of the HF patients are diagnosed with diastolic dysfunction [[2], [3], [4], [5]]. Diastolic dysfunction is commonly associated with cardiovascular, metabolic, and inflammatory comorbidities [6]. For instance, age, hypertension, diabetes mellitus, obesity, chronic renal failure, and LV hypertrophy are the major risk factors for diastolic dysfunction [7,8]. Recent studies demonstrate that persistent or progression of diastolic dysfunction, especially with co-existing comorbidities, promotes the development of heart failure in aging population [9,10]. However, currently available and effective treatment for HFrEF have failed to show promising results in patients with diastolic dysfunction [11]. Clinical studies reveal that patients with HFpEF have coronary microvascular rarefaction and more cardiac hypertrophy than age-matched patients without clinical diagnosis of coronary artery disease and heart failure [6]. Despite the clinical importance of HFpEF, our understanding of its pathophysiology and molecular mechanism is incomplete.
Sirtuins are a family of Class III histone deacetylases (HDACs) that require NAD+ for their lysine residue deacetylase activity [12,13]. Sirtuins regulate cellular homeostasis, including energy metabolism and reactive oxygen species (ROS) [14,15]. Of the Sirtuin family, SIRT3 is primarily localized to the mitochondria in metabolic active organs, including liver, adipose tissue, and heart, where it regulates mitochondrial function and cellular metabolism [[15], [16], [17], [18]]. Increased SIRT3 expression protects cardiomyocytes, pancreatic cells, and neurons from inflammation and apoptosis by reducing oxidative stress [[19], [20], [21], [22]]. SIRT3 levels have been shown to decrease in human cardiac fibroblasts isolated from controls and patients with HF [23]. Hirschey and colleagues report that ablation of SIRT3 in mice impairs glucose tolerance and develops hepatic steatosis and metabolic syndrome [24,25]. In our previous study, we found that ablation of SIRT3 causes coronary microvascular dysfunction and increases ischemic injury in the heart [26]. Moreover, specific deletion of endothelial Sirt3 impairs glycolysis and causes a diastolic dysfunction in mice [27]. Koentges and colleagues report that SIRT3 deficiency causes mitochondrial and contractile dysfunction in the heart [28]. These studies indicate a critical role of SIRT3 in the development of cardiac dysfunction.
Hypoxia triggers the activation of hypoxia-inducible factors (HIFs) and the expression of many genes involving in glucose uptake, glycolysis, erythropoiesis, and angiogenesis [[29], [30], [31]]. Prolyl hydroxylases (PHDs) play an important role in the regulation of HIFs [32,33]. Deactivation of PHD1 reduces oxygen consumption and mitochondrial oxidative stress and protects against muscle ischemic necrosis [34]. However, the consequence of administering PHD inhibitor on the diastolic dysfunction is unclear. In the present study, we hypothesized that inhibition of PHDs that mimics induction of hypoxia tolerance is protective against the diastolic dysfunction in the SIRT3 deficient mice. Our study reveals that the expression of PHD1 and PHD2 is significantly upregulated in the SIRT3 deficient mice. Moreover, treatment with PHD inhibitor DMOG reprograms endothelial metabolism, improves coronary microvascular function and diastolic function in global SIRT3 knock-out (KO) mice and endothelial-specific SIRT3 KO mice.
Section snippets
Methods
See Online Data Supplement for detailed methods and materials.
SIRT3 KO mice develops diastolic dysfunction
We examined whether SIRT3 KO mice developed a diastolic dysfunction in the presence of impaired CFR. Pulse-wave (PW) Doppler measurements indicated that the isovolumic relaxation time (IVRT) was significantly increased in SIRT3 KO mice (Fig. 1A and B). In addition, the calculated myocardial performance index was significantly elevated (Fig. 1B). The mitral valve inflow velocity during early diastolic (E) phase was similar between WT and SIRT3 KO mice, but it was associated with a significant
Discussion
This study demonstrates that SIRT3 deletion results in diastolic dysfunction that is associated with upregulation of PHD1 and PHD2 and alterations in endothelial cell metabolism. These abnormalities lead to coronary microvascular dysfunction manifested as reduced CFR and subsequent diastolic dysfunction in mice. Pharmacological inhibition of PHDs by DMOG improves endothelial glycolytic metabolism and angiogenesis, reverses coronary dysfunction and pre-existed diastolic dysfunction. These
Conclusion
Our study provides the first insight into the potential role of PHD on SIRT3 deficiency-induced diastolic dysfunction. Our results suggest that loss of SIRT3 impairs PHD/HIF signaling pathway and alters cell metabolism. Inhibition of PHD can improve endothelial metabolic homeostasis and reverse pre-existed diastolic dysfunction. This study provides a potential therapeutic strategy that clinically relevant PHD inhibition by DMOG for patients with diastolic dysfunction associated with coronary
Author contributions
X. He, H. Zeng, R. J. Roman, and JX Chen designed the research; X. He and H. Zeng performed the research and analyzed the data; X. He and JX Chen wrote the paper.
Funding
This study was supported by grants from NIH grant 2R01HL102042-05 and University of Mississippi Medical Center Intramural Research Support Program to J.X. Chen.
Acknowledgments
The authors thank Dr. Eric Verdin at Gladstone Institute of California for providing the original SIRT3flox/flox mice.
Conflicts of interest
The authors have no conflicts of interest associated with this manuscript.
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