Role of Endothelial Nitric Oxide Synthase and Collagen Metabolism in Right Ventricular Remodeling due to Pulmonary Hypertension

Abstract

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp dynamically. 6 Under normal conditions, smaller and crescentshaped RV wall thickness is only one-fifth of that of the LV, and the RV has a higher proportion of the α-myosin heavy chain isoform that results in a more rapid but less energy efficient contraction. 7 Furthermore, coronary blood flow to the RV is roughly balanced between systolic and diastolic time periods, while a majority of the flow occurs in the diastole in the LV wall. 8 The RV has greater resistance to ischemia compare to the LV and has better adaptation to volume overload states, while LV has better adaptation to pressure overload states. 9 Thus, the increase in RV afterload might not be similar to that in the LV in response to pharmacological therapies. 10 Nitric oxide (NO) synthesized by endothelial cells (eNOS) is an important downstream signaling molecule in the cardiovascular system. 11 The protective effects of NO on vascular ulmonary hypertension (PH) is a fatal disease characterized by increased pulmonary vascular resistance, resulting in an impaired right ventricular (RV) function due to increased RV afterload and contractile abnormality of the RV. 1-3 The disease is progressive in nature, leading to RV hypertrophy (RVH) and ultimately RV failure and death within less than 5 years after diagnosis. 1,4 Mortality of PH patients is closely associated with alterations in RV hemodynamic variables, such as mean pulmonary artery pressure, mean right atrial pressure and cardiac index. 4 Despite the recent advances in medical therapy for PH, there is no cure for the disorder, and cellular and molecular mechanisms of RV remodeling and failure in PH still remain to be fully elucidated. 5 RV is different from left ventricle (LV) embryologically, macroscopically, ultrastructurally, biochemically and hemo- Background: Pulmonary hypertension (PH) causes elevated right ventricular (RV) systolic pressure, RV remodeling and finally RV failure to death. However, the mechanisms of RV remodeling in PH remain to be fully elucidated.

Limiting collagen turnover via collagenase-resistance attenuates right ventricular dysfunction and fibrosis in pulmonary arterial hypertension

“…Finally, perivascular fibrosis was quantified using the collagen area surrounding a vessel divided by the total vessel area (Nergui et al. ).…”

Inflammatory Mediators Drive Adverse Right Ventricular Remodeling and Dysfunction and Serve as Potential Biomarkers

“…Moreover, in a model of severe PH caused by a single injection of vascular endothelial growth factor (VEGF) receptors blocker in athymic rats, macrophage infiltration was associated with adverse RV remodeling and dysfunction ( Guihaire et al, 2017 ). Increased macrophage recruitment has also been demonstrated in RV autopsy samples from PAH patients with RV failure ( Nergui et al, 2014 ). Notably, autopsy samples from patients with SSc-associated PAH exhibited significantly more macrophage infiltration in the right ventricle as compared with those from patients with idiopathic PAH ( Overbeek et al, 2010 ).…”

Epigenetic Regulation of Pulmonary Arterial Hypertension-Induced Vascular and Right Ventricular Remodeling: New Opportunities?

“…In PAH, the inflammatory response in the RV is marked by an increase in infiltrating CD45 + /CD68 + cells [77] and pro-inflammatory cytokine signaling involving molecules such as tumor necrotic factor α (TNF-α) and interleuking-1 (IL-1) family members [78,79]. Whereas increased and sustained inflammation during RV hypertrophy appears to be beneficial at short term by leading to increased angiogenesis, it does affect CM functionality at long term, by decreasing contractility and increasing ROS production [80,81].…”