Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease

Abstract

Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric oxide (NO) and natriuretic peptide (NP) coupled signaling, stimulating phosphorylation changes by protein kinase G (PKG). Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease1,2. However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation3. Furthermore, though PDE5A regulates NO-generated cGMP4,5, NO-signaling is often depressed by heart disease6. PDEs controlling NP-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A7,8 is expressed in mammalian heart including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates NP rather than NO-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neuro-hormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of NO-synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phospho-proteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signaling independent of the NO-pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target.

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

“…Western blot analysis was used to determine protein levels as previously described6, 16, 19, 24 in buffer containing 150 mmol/L NaCl, 10 mmol/L Tris pH 7.4, 1 mmol/L EDTA, 1% Triton X‐100, and protease/phosphatase inhibitors (Halt, Thermo Scientific). After sonication, the lysates were centrifuged at 17 000 g for 10 minutes to remove insoluble material and sample concentration was then determined by Bradford assay (Bio‐Rad).…”

What people with Down Syndrome can teach us about cardiopulmonary disease

“…In another example, Hsa21-encoded PDE9a hydrolyses cGMP and is a major determinant of intracellular cGMP levels important for signalling cascades. PDE9a overexpression contributes to maladaptive hypertrophy and cardiac failure in humans and in a mouse model of aortic stenosis [143]. Conversely, expression of miR-99a correlates closely with cardiac function in mice, and overexpression of miR-99a attenuates both cardiomyocyte hypertrophy in vitro and aortic stenosis-associated cardiac hypertrophy in vivo [144].…”

CYP 2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPK α2 and enhancing nuclear translocation of Akt1

“…The increase in ANP that occurs with cardiac hypertrophy might help compensate for the increase in afterload. In the past few years, studies have revealed that the antihypertrophic effect of ANP is mediated by the guanylylcyclase‐A receptor and cGMP production (Klaiber et al ., 2011; Lee et al ., 2015). Furthermore, ANP has been used to reduce cardiac remodeling after myocardial infarction (Kuga et al ., 2003).…”