Abstract
Atherosclerosis is strongly associated with cardiac dysfunction and heart failure. Besides microvascular dysfunction and diminishment of the cardiac nitric oxide-Protein Kinase G (NO-PKG) pathway, recent evidence suggests that phosphodiesterase 9A (PDE9A) enzyme has an unfavorable role in pathological changes. Here, we characterized a rabbit model that shows cardiac dysfunction as a result of an atherogenic diet, and examined the myocardial PDE9A signaling. Rabbits were divided into Control (normal diet) and HC (atherogenic diet) groups. Cardiac function was evaluated by echocardiography. Vascular function was assessed, along with serum biomarkers. Histological stains were conducted, expression of selected proteins and cyclic guanosine monophosphate (cGMP) levels were determined. Signs of diastolic dysfunction were shown in HC animals, along with concentric hypertrophy and interstitial fibrosis. Endothelial function was diminished in HC rabbits, along with marked reduction in the aortic lumen, and increased left ventricle outflow tract (LVOT) pressures. A significant increase was shown in myocardial PDE9A levels in HC animals with unchanged vasodilator-stimulated phosphoprotein (VASP) phosphorylation and cGMP levels. Upregulation of PDE9A may be associated with early stage of cardiac dysfunction in atherosclerotic conditions. Since PDE9A is involved in cGMP degradation and in deactivation of the cardioprotective PKG signaling pathway, it may become an encouraging target for future investigations in atherosclerotic diseases.
Highlights
Dyslipidemia is a well-documented risk factor for cardiovascular disorders and many different preclinical and clinical trials proved that the elevation of low-density lipoprotein (LDL) serum level causes atherosclerotic cardiovascular disease [1]
The downregulation of this pathway may be greatly responsible for diastolic dysfunction (DD), which is the precursor of diastolic heart failure (HF with preserved ejection fraction, HFpEF) and characteristic in systolic heart failure as well (HF with reduced ejection fraction, HFrEF) [7,8]
Decreased levels of natriuretic peptides (NPs) or degradation of NP-derived cyclic guanosine monophosphate (cGMP) by phosphodiesterase type 9A (PDE9A) contributes to the pathology of HFpEF, as it was shown on PDE9A global knockout mice that underwent a pressure-overload technique [13]
Summary
Dyslipidemia is a well-documented risk factor for cardiovascular disorders and many different preclinical and clinical trials proved that the elevation of low-density lipoprotein (LDL) serum level causes atherosclerotic cardiovascular disease [1]. Decreased levels of natriuretic peptides (NPs) or degradation of NP-derived cGMP by PDE9A contributes to the pathology of HFpEF, as it was shown on PDE9A global knockout mice that underwent a pressure-overload technique [13]. Altering this pathway could lead to a new direction in drug discovery—i.e., by pharmacological augmentation of the NP-derived cGMP system, besides the well-known PDE5 inhibitors. In recent years, this theory was further evidenced by the fact that enhancement of NP signaling by inhibiting neprilysin, (the enzyme that metabolizes natriuretic peptides), have had promising results in clinical trials (PARAGON-HF trial) [14]
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