Alterations in cGMP, soluble guanylate cyclase, phosphodiesterase 5, and B‐type natriuretic peptide induced by chronic increased pulmonary blood flow in lambs

Oishi, Peter; Sharma, Shruti; Grobe, Albert C.; Azakie, Anthony; Harmon, Cynthia; Johengen, Michael J.; Hsu, Jong Hau; Fratz, Sohrab; Black, Stephen M.; Fineman, Jeffrey R.

doi:10.1002/ppul.20696

Cited by 16 publications

(15 citation statements)

References 52 publications

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“…Lambs with increased PBF have increased levels of cGMP, unlike the GW9662-treated lambs. This increase is mediated via stimulation of particulate guanylate cyclase activity by BNP [30] and despite increased PDE5 activity [31]. We did not find changes in PDE5 activity with GW9662-treatment alone.…”

Section: Discussionmentioning

confidence: 69%

Chronic inhibition of PPAR-γ signaling induces endothelial dysfunction in the juvenile lamb

Sharma

Barton

Rafikov

et al. 2013

Pulmonary Pharmacology & Therapeutics

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We have recently shown that the development of endothelial dysfunction in lambs with increased pulmonary blood flow (PBF) correlates with a decrease in peroxisome proliferator activated receptor-γ (PPAR-γ) signaling. Thus, in this study we determined if the loss of PPAR-γ signaling is necessary and sufficient to induce endothelial dysfunction by exposing lambs with normal PBF to the PPAR-γ antagonist, GW9662. Two-weeks of exposure to GW9662 significantly decreased both PPAR-γ protein and activity. In addition, although eNOS protein and nitric oxide metabolites (NOx) were significantly increased, endothelial dependent pulmonary vasodilation in response to acetylcholine was attenuated, indicative of endothelial dysfunction. To elucidate whether downstream mediators of vasodilation were impaired we examined soluble guanylate cyclase (sGC)- α and β subunit protein, cGMP levels, and phosphodiesterase 5 (PDE5) protein and activity, but we found no significant changes. However, we found that peroxynitrite levels were significantly increased in GW9662-treated lambs and this correlated with a significant increase in protein kinase G-1α (PKG-1α) nitration and a reduction in PKG activity. Peroxynitrite is formed by the interaction of NO with superoxide and we found that there was a significant increase in superoxide generation in GW9662-treated lambs. Further, we identified dysfunctional mitochondria as the primary source of the increased superoxide. Finally, we found that the mitochondrial dysfunction was due to a disruption in carnitine metabolism. We conclude that loss of PPAR-γ signaling is sufficient to induce endothelial dysfunction confirming its important role in maintaining a healthy vasculature.

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Section: Discussionmentioning

confidence: 69%

Chronic inhibition of PPAR-γ signaling induces endothelial dysfunction in the juvenile lamb

Sharma

Barton

Rafikov

et al. 2013

Pulmonary Pharmacology & Therapeutics

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“…25 In experimental animals, increased pulmonary blood flow and associated pulmonary hypertension are accompanied by raised circulating levels of BNP and cGMP. 26 The levels of these 2 factors also were closely correlated in patients with Eisenmenger syndrome, potentially obscuring any direct association between NO and cGMP production. Increased circulating inflammatory mediators also accompanied raised plasma NO x levels, and cytokine-inducible NO synthase (NOS) expression has been described in pulmonary arteries and cardiac tissues of patients with flow-associated pulmonary hypertension and cyanotic congenital heart disease.…”

Section: Discussionmentioning

confidence: 99%

Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension

et al. 2008

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Background— Impaired endothelial homeostasis underlies the pathophysiology of pulmonary arterial hypertension (PAH). We speculated that PAH patients are deficient in circulating endothelial progenitor cells (EPCs), potentially contributing to endothelial dysfunction and disease progression. Methods and Results— We recruited 41 patients with Eisenmenger syndrome (13 with Down syndrome), 55 with idiopathic PAH, and 47 healthy control subjects. Flow cytometry and in vitro assays were used to quantify EPCs and to assess cell function. The number of circulating CD34 + , CD34 + /AC133 + , CD34 + /KDR + , and CD34 + /AC133 + /KDR + progenitor cells was low in Eisenmenger patients compared with healthy control subjects, and those with Down syndrome displayed even fewer EPCs. Reductions in EPC numbers correlated with New York Heart Association functional class, 6-minute walk distance, and plasma brain-type natriuretic peptide levels. The capacity of cultured peripheral blood mononuclear cells to form colonies and incorporate into tube-like structures was impaired in Eisenmenger patients. Idiopathic PAH patients had reduced numbers of EPCs, and the number of circulating EPCs correlated with invasive hemodynamic parameters in this cohort. Levels of immune inflammatory markers, cGMP, stable nitric oxide oxidation products, and asymmetric dimethylarginine were abnormal in patients with PAH and related to numbers of EPCs. Within the idiopathic PAH population, treatment with the phosphodiesterase inhibitor sildenafil was associated with a dose-dependent rise in EPC numbers, resulting in levels consistently above those found with other therapies. Conclusions— Circulating EPC numbers are reduced in 2 well-characterized forms of PAH, which also exhibit raised levels of inflammatory mediators. Sildenafil treatment may represent a pharmacological means of increasing circulating EPC numbers long-term.

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“…Induction of PDE5 has been observed in rat models of mesenteric occlusion where functional studies suggested that it attenuates increased NO signaling (Zhang et al, 2009). PDE5 is also induced in heart and lung in response to chronic pressure overload (Oishi et al, 2007; Vandenwijngaert et al, 2013), and in resistance pulmonary arteries to hyperoxia (Farrow et al, 2008), and underscores the complex changes in gene expression that determine signaling through the NO/cGMP signaling pathway. To the best of our knowledge PDE5 inhibitor drugs have not been tested for salutary effects on coronary blood flow in this model of chronic coronary occlusion.…”

Section: Discussionmentioning

confidence: 98%

Myosin phosphatase isoforms and related transcripts in the pig coronary circulation and effects of exercise and chronic occlusion

Zheng

Heaps

Fisher

2015

Microvascular Research

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Myosin phosphatase (MP) is a key target of signaling pathways that regulate smooth muscle tone and blood flow. Alternative splicing of MP targeting subunit (MYPT1) exon 24 (E24) generates isoforms with variable presence of a C-terminal leucine zipper (LZ) required for activation of MP by NO/cGMP. Here we examined the expression of MP and associated genes in a disease model in the coronary circulation. Female Yucatan miniature swine remained sedentary or were exercise-trained beginning eight weeks after placement of an ameroid constrictor around the left circumflex (LCX) artery. Fourteen weeks later epicardial arteries (~1 mm) and resistance arterioles (~125 µm) were harvested and assayed for gene expression. MYPT1 isoforms were distinct in the epicardial arteries (E24−/LZ+) and resistance arterioles (E24+/LZ−) and unchanged by exercise training or coronary occlusion. MYPT1, CPI-17 and PDE5 mRNA levels were not different between arteries and arterioles while Kir2.1 and eNOS were 6.6-fold and 3.9-fold higher in the arterioles. There were no significant changes in transcript abundance in epicardial arteries of the collateralized (LCX) vs. non-occluded left anterior descending (LAD) territories, or in exercise-trained vs. sedentary pigs. There was a significant 1.2 fold increase in CPI-17 in collateral-dependent arterioles, independent of exercise, and a significant 1.7 fold increase in PDE5 in arterioles from exercise-trained pigs, independent of occlusion. We conclude that differences in MYPT1 E24 (LZ) isoforms, eNOS, and Kir2.1 distinguish epicardial arteries and resistance coronary arterioles. Up-regulation of coronary arteriolar PDE5 by exercise and CPI-17 by chronic occlusion could contribute to altered vasomotor responses and requires further study.

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Alterations in cGMP, soluble guanylate cyclase, phosphodiesterase 5, and B‐type natriuretic peptide induced by chronic increased pulmonary blood flow in lambs

Abstract: Alterations in sGC subunit protein expression during the first post-natal month, and increased BNP levels during the second post-natal month contribute to elevations in plasma and lung tissue cGMP in lambs with increased pulmonary blood flow.

Cited by 16 publications

References 52 publications

Chronic inhibition of PPAR-γ signaling induces endothelial dysfunction in the juvenile lamb

Chronic inhibition of PPAR-γ signaling induces endothelial dysfunction in the juvenile lamb

Circulating Endothelial Progenitor Cells in Patients With Eisenmenger Syndrome and Idiopathic Pulmonary Arterial Hypertension

Myosin phosphatase isoforms and related transcripts in the pig coronary circulation and effects of exercise and chronic occlusion

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