Endothelial C-type natriuretic peptide maintains vascular homeostasis

PMCID: PMC4151218Wellcome Trust (084449/Z/07/Z and 078496/Z/05/Z

Phosphodiesterase 2 inhibition preferentially promotes NO/guanylyl cyclase/cGMP signaling to reverse the development of heart failure.

Heart failure (HF) is a shared manifestation of several cardiovascular pathologies, including hypertension and myocardial infarction, and a limited repertoire of treatment modalities entails that the associated morbidity and mortality remain high. Impaired nitric oxide (NO)/guanylyl cyclase (GC)/cyclic guanosine-3',5'-monophosphate (cGMP) signaling, underpinned, in part, by up-regulation of cyclic nucleotide-hydrolyzing phosphodiesterase (PDE) isozymes, contributes to the pathogenesis of HF, and interventions targeted to enhancing cGMP have proven effective in preclinical models and patients. Numerous PDE isozymes coordinate the regulation of cardiac cGMP in the context of HF; PDE2 expression and activity are up-regulated in experimental and human HF, but a well-defined role for this isoform in pathogenesis has yet to be established, certainly in terms of cGMP signaling. Herein, using a selective pharmacological inhibitor of PDE2, BAY 60-7550, and transgenic mice lacking either NO-sensitive GC-1α (GC-1α-/-) or natriuretic peptide-responsive GC-A (GC-A-/-), we demonstrate that the blockade of PDE2 promotes cGMP signaling to offset the pathogenesis of experimental HF (induced by pressure overload or sympathetic hyperactivation), reversing the development of left ventricular hypertrophy, compromised contractility, and cardiac fibrosis. Moreover, we show that this beneficial pharmacodynamic profile is maintained in GC-A-/- mice but is absent in animals null for GC-1α or treated with a NO synthase inhibitor, revealing that PDE2 inhibition preferentially enhances NO/GC/cGMP signaling in the setting of HF to exert wide-ranging protection to preserve cardiac structure and function. These data substantiate the targeting of PDE2 in HF as a tangible approach to maximize myocardial cGMP signaling and enhancing therapy.British Heart Foundation Grant PG/10/077/28554

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Manganese Carbonyls Bearing Tripodal Polypyridine Ligands as Photoactive Carbon Monoxide-Releasing Molecules

The recently discovered cytoprotective action of CO has raised interest in exogenous CO-releasing materials (CORMs) such as metal carbonyls (CO complexes of transition metals). To achieve control on CO delivery with metal carbonyls, we synthesized and characterized three Mn­(I) carbonyls, namely, [Mn­(tpa)­(CO)₃]­ClO₄ [<b>1</b>, where tpa = tris­(2-pyridyl)­amine], [Mn­(dpa)­(CO)₃]Br [<b>2</b>, where dpa = <i>N</i>,<i>N</i>-bis­(2-pyridylmethyl)­amine], and [Mn­(pqa)­(CO)₃]­ClO₄ [<b>3</b>, where pqa = (2-pyridylmethyl)­(2-quinolylmethyl)­amine], by crystallography and various spectroscopic techniques. All three carbonyls are sensitive to light and release CO when illuminated with low-power UV (5–10 mW) and visible (λ > 350 nm, ∼100 mW) light. The sensitivity of <b>1–3</b> to light has been assessed with respect to the number of pyridine groups in their ligand frames. When a pyridine ring is replaced with quinoline, extended conjugation in the ligand frame increases the absorptivity and makes the resulting carbonyl <b>3</b> more sensitive to visible light. These photosensitive CORMs (photoCORMs) have been employed to deliver CO to myoglobin under the control of light. The superior stability of <b>3</b> in aqueous media makes it a photoCORM suitable for inducing vasorelaxation in mouse aortic muscle rings

I kappa B Kinase Inhibitor Attenuates Sepsis-Induced Cardiac Dysfunction in CKD

Patients with CKD requiring dialysis have a higher risk of sepsis and a 100-fold higher mortality rate than the general population with sepsis. The severity of cardiac dysfunction predicts mortality in patients with sepsis. Here, we investigated the effect of preexisting CKD on cardiac function in mice with sepsis and whether inhibition of I\u3baB kinase (IKK) reduces the cardiac dysfunction in CKD sepsis. Male C57BL/6 mice underwent 5/6 nephrectomy, and 8 weeks later, they were subjected to LPS (2 mg/kg) or sepsis by cecal ligation and puncture (CLP). Compared with sham operation, nephrectomy resulted in significant increases in urea and creatinine levels, a small (P<0.05) reduction in ejection fraction (echocardiography), and increases in the cardiac levels of phosphorylated I\u3baB\u3b1, Akt, and extracellular signal-regulated kinase 1/2; nuclear translocation of the NF-\u3baB subunit p65; and inducible nitric oxide synthase (iNOS) expression. When subjected to LPS or CLP, compared with sham-operated controls, CKD mice exhibited exacerbation of cardiac dysfunction and lung inflammation, greater increases in levels of plasma cytokines (TNF-\u3b1, IL-1\u3b2, IL-6, and IL-10), and greater increases in the cardiac levels of phosphorylated IKK\u3b1/\u3b2 and I\u3baB\u3b1, nuclear translocation of p65, and iNOS expression. Treatment of CKD mice with an IKK inhibitor (IKK 16; 1 mg/kg) 1 hour after CLP or LPS administration attenuated these effects. Thus, preexisting CKD aggravates the cardiac dysfunction caused by sepsis or endotoxemia in mice; this effect may be caused by increased cardiac NF-\u3baB activation and iNOS expression