C-type Natriuretic Peptide Ameliorates Monocrotaline-induced Pulmonary Hypertension in Rats

Abstract

C-type natriuretic peptide (CNP) has been shown to act as a local regulator of vascular tone and remodeling. We investigated whether CNP ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Rats received a continuous infusion of CNP or placebo. Significant pulmonary hypertension developed 3 weeks after MCT. However, infusion of CNP significantly attenuated the development of pulmonary hypertension and vascular remodeling. Neither systemic arterial pressure nor heart rate was altered. Interestingly, CNP enhanced Ki-67 expression, a marker for cell proliferation, in pulmonary endothelial cells and augmented lung tissue content of endothelial nitric oxide synthase. CNP significantly suppressed apoptosis of pulmonary endothelial cells, decreased the number of monocytes/macrophages, and inhibited expression of plasminogen activator inhibitor type 1, a marker for fibrinolysis impairment, in the lung. In addition, CNP significantly increased the survival rate in MCT rats. Finally, infusion of CNP after the establishment of pulmonary hypertension also had beneficial effects on hemodynamics and survival. In conclusion, infusion of CNP ameliorated MCT-induced pulmonary hypertension and improved survival. These beneficial effects may be mediated by regeneration of pulmonary endothelium, inhibition of endothelial cell apoptosis, and prevention of monocyte/macrophage infiltration and fibrinolysis impairment.

Important Role of Endogenous Erythropoietin System in Recruitment of Endothelial Progenitor Cells in Hypoxia-Induced Pulmonary Hypertension in Mice

“…36,37 In line with these findings, we observed that lack of EpoR expression on pulmonary endothelium accelerates pulmonary vascular remodeling in EpoR Ϫ/Ϫ rescued mice; this occurrence may be partly due to the lack of direct effects of Epo on pulmonary endothelial cells. 38 -40 By contrast, the expression of EpoR was upregulated by hypoxia in wild-type mice.…”

Gene Delivery of Cytochrome P450 Epoxygenase Ameliorates Monocrotaline-Induced Pulmonary Artery Hypertension in Rats

“…Gene transfer with endothelial nitric oxide synthase attenuated MCT-induced pulmonary hypertension in rats (28). Other pharmacologic treatments that were effective in this PAH model were also associated with an upregulation of eNOS (3,24,25). Thus, the therapeutic effects of CYP2J2 delivery on pulmonary hypertension may be mediated by protection of the endothelium through a restoration of the expression of eNOS, at least in a part.…”

“…The pathologic changes of PAH include endothelial cell injury and apoptosis, medial hypertrophy, infiltration by inflammatory cells, and thrombosis in small pulmonary arteries (2,3). Endothelial dysfunction is characterized by an imbalance of vasodilator and vasoconstrictor factors, including an altered ratio of thromboxane and prostacyclin, decreased expression of endothelial NO synthase (eNOS), and increased endothelin-1 (ET-1) (4).…”

ATP-Sensitive Potassium Channel Activation Induces Angiogenesis In Vitro and In Vivo

“…CNP is a member of the natriuretic peptide family (Margulies and Burnett, 2006;Lumsden et al, 2010;Baliga et al, 2012) and is widely expressed in various tissues, including the vasculature, especially by the endothelial cells (Baliga et al, 2012;Moyes et al, 2014). CNP is thought to exert an overall vascular protective role: it can fine-tune vascular cell growth (Khambata et al, 2011), establish tone and flow in resistance arteries (Villar et al, 2007;Lumsden et al, 2010), influence vessel wall remodeling (Itoh et al, 2004;Moyes et al, 2014), accelerate re-endothelialization (Ohno et al, 2002), or reduce inflammation (Itoh et al, 2004;Lumsden et al, 2010;Moyes et al, 2014). In contrast to CNP-triggered vasodilatation, directly linked to its stimulation of K ATP activity (Burley et al, 2014), the mechanisms underlying CNP's angiogenic effects are still poorly characterized.…”