Cardiovascular Disease

Cardiovascular disease describes a range of conditions that affect your cardiovascular system, especially with aging. This includes coronary artery disease, atherosclerosis, arrhythmias, congenital heart disease, cerebrovascular disease, myocardial infarction, etc. Ramatroban can potentially treat and prevent cardiovascular disease.

Atherosclerosis

Thromboxane A2 (TxA2) is significantly increased in obesity (Petrucci et al, 2019) and plays a role in the pathogeneses of atherosclerosis and cardiovascular disease. TP receptor antagonism has been shown to retard the progression of atherosclerotic disease by diminishing impaired vascular reactivity responses normally associate with hypercholesterolemia (Pfisher, 2007). In cholesterol-fed rabbits lacking only vascular TP receptors, the overall incidence of aortic lesions were small after 3 week of cholesterol feedings, results indicating a reduction in lesions in the vascular TP knockout compared to the vascular TP positive rabbits on a cholesterol diet (Pfisher, 2007).  Furthermore, TP receptor blockade by ramatroban during 4 weeks after balloon angioplasty in the atherosclerotic rabbits prevented macrophage infiltration through MCP-1 downregulation and neointimal formation (Ishizuka et al, 2006). Ramatroban also improved the vascular response in vivo at acetylcholine in hypercholesterolemia rabbits by blocking the action of 8-iso-prostaglandin F2 alpha (Ishizuka et al, 2003).

 

Low Density Lipoproteins: TP receptor antagonism is more effective than combined inhibition of COX-1 and COX-2 in retarding atherogenesis in apobec-1/low density lipoprotein receptor (LDLR) double knockout mice (208). Under normal conditions, macrophages take up low-density lipoproteins (LDLs) through LDL receptors (LDLRs). Under conditions that lead to the accumulation of oxidised LDL (oxLDL) or other forms of modified LDL, macrophages become highly efficient at taking up these particles through the action of scavenger receptors (SR)-A, −BI and CD36, which have evolved as molecular pattern recognition receptors to mediate phagocytosis of pathogens and apoptotic cells (reviewed by Hazen, 2008). The accumulation of LDL derivatives inside macrophages inhibits the surface expression of classical LDLRs but not of scavenger receptors (Brown and Goldstein, 1986). Thus, macrophages conserve the capacity to accumulate very large amounts of oxLDL-derived lipids and become lipid-loaded foam cells, which play a major role in atherosclerosis (Valledor et al, 2010). 

Nitric Oxide: Following arterial injury, nitric oxide (NO) has been shown to serve many vasoprotective roles, including inhibition of platelet aggregation and adherence to the site of injury, inhibition of leukocyte adherence, inhibition of vascular smooth muscle cell proliferation and migration, and stimulation of endothelial cell growth (Kibbe et al, 1999). NO is an inhibitor of platelet activation via phosphorylation of the TP receptor. In both vascular smooth muscle cells and platelets, the vasodilatory and platelet inhibitory effects of NO are known to be mediated by cGMP, which inhibits phospholipase C activation, inositol 1,4,5-triphosphate generation, and [Ca2+]i mobilization (Liu et al, 2020). NO stimulates production of cGMP and activated cGMP-dependent protein kinase or G kinase (Liu et al, 2020). TxA2 is known to directly inhibits inducible nitric oxide synthase (Shiokoshi et al, 2002), and inhibits endothelial nitric oxide synthase via ROCK-PTEN signaling (Zhao et al, 2017). In fact, nitrite accumulation in rat VSMCs, which was suppressed with a TxA2 mimetic, was increased by ramatroban, as a TP receptor antagonist (Shiokoshi et al, 2002). Therefore, TP receptor antagonism with ramatroban will increase nitric oxide production, which has beneficial effects in atherosclerosis. 

Cell Adhesion: Under the effect of oxLDL, endothelial cells express adhesion molecules, including E- and P-selectins, which interact with integrins expressed on the surface of circulating monocytes, thus facilitating monocyte tethering and rolling on the endothelial layer. This process is followed by firm adhesion of monocytes on endothelial cells mediated by endothelial expression of vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Finally, transmigration through the endothelium involves the interaction of junctional adhesion molecules (JAM) and connexins (reviewed by Galkina and Ley, 2007). Endothelial transmigration of monocytes is also promoted by chemokines, such as monocyte chemoattractant protein 1 (MCP-1) and CCL5 (also known as Rantes). The chemokine C-C receptors CCR2 and CCR5 are expressed in monocytes and play an important role in atherosclerosis by binding to MCP-1 and CCL5, respectively. Macrophage migration inhibitory factor (MIF) is a cytokine that plays a regulatory role in monocyte adhesion and migration and in macrophage proliferation. Increased expression of MIF has been demonstrated in human atherosclerotic lesions, whereas the absence of the gene encoding MIF reduces atherosclerosis in mice (reviewed by Noels et al., 2009) (Valledor et al, 2010).

Thromboxane plays a major role in cell adhesion and migration. First, the expression of VCAM-1, ICAM-1 and ELAM-1 on the surface of human umbilical vein endothelial cells (HUVEC) is enhanced by TP receptor agonism. 24 hours after the addition of a TxA2 mimetic (U-44619) the expression of VCAM-1, ICAM-1, and ELAM-1 was significantly intensified. It was concluded that ICAM-1 or ELAM-1 expression of HUVEC stimulated via TXA2 receptors is augmented by induction of NF-κB and AP-1 binding activity through the PKC system, and that VCAM-1 expression is augmented by induction of NF-κB binding activity (Ishizuka, Kawakami, Hidaka, et al, 1998). Second, U46619 also induces MCP-1 expression in endothelial cells. MCP-1 mRNA was barely detectable in unstimulated HUVEC, but U46619 induced a dose-dependent increase in the accumulation of MCP-1 mRNA within 6 h (Ishizuka et al, 2000) TP receptor antagonism with ramatroban suppresses the expression of MCP-1 and adhesion molecules in endothelial cells and prevents exacerbation of inflammation by blocking these responses (Ishizuka et al, 2006). Third, P-selectin is normally stored in the a granules of platelets and is rapidly expressed on the surface of activated platelets. It was demonstrated that the percentage of P-selectin-positive platelets in TP receptor knockout mice on day 1 was significantly reduced compared with that in wild type mice (Matsui et al, 2012). It is worth mentioning that platelet-leukocyte adhesion via P-selectin leads to further production of TxA2 and leukotriene C4 (Maugeri et al, 1994). TxA2 also regulated E-selectin expression on endothelial cells, which is blocked by a TxA2 synthase inhibitor (Kameda et al, 1995). Finally, TxA2 plays a role in the action of MIF on macrophage migration which was blocked by a TxA2 synthase inhibitor (Jakubowski and Pick, 1983). Therefore, ramatroban, as a TP receptor antagonist, can prevent the adhesion and migration of monocytes in atheroclerosclerosis, perhaps inhibiting cell entry into the tunica intima. 

Angiogenesis: Furthermore, neovascularization in atherosclerotic lesions plays a major role in plaque growth and instability (210). Endothelial cell growth and monocyte adhesion to endothelial cells is an early event in atherosclerosis (Obikane et al, 2010). VEGF and FGF2 (also known as bFGF) are known for inducing both sprouting and intussusceptive angiogenesis (Hoeben et al, 2004; Folkman, 2001; Hillen and Griffioen, 2007, Makanya et al, 2009). FGF2 and VEGF are found to increased TxA2 synthesis in endothelial cells three to five fold (Nie et al, 2000). TxA2 antagonism inhibits VEGF or FGF2 induced endothelial migration. A study by Level et al. treated rat aortic explants with U-44619 or TP receptor antagonists and thromboxane synthase inhibitors. U-46619 significantly enhances vessel sprouting whereas aortic rings treated with thromboxane synthase antagonists demonstrate a significant decrease in vessel sprouting, which is not reversed by the addition of VEGF (de Leval et al, 2006). Therefore, TxA2 functions as a critical intermediary of angiogenesis in atherosclerosis via the TP receptor (Daniel et al, 1999), which can be blocked by ramatroban, a TP receptor antagonist.

Thrombosis: At later stages of atherosclerosis, foam cells express high levels of cycloxygenases (COX)-1 and -2 (reviewed by Cipollone et al., 2008). These are enzymes that generate pro-inflammatory prostaglandins and TXA2, which induce vasoconstriction and platelet aggregation. Inflammatory mediators also activate resident cells in the lesion and the secretion of proteolytic enzymes by macrophages contributes to plaque erosion and rupture by forming a surface on which activated platelets may initiate thrombosis and amplify inflammation, thereby leading to stroke and myocardial infarction (Valledor et al, 2010). Ramatroban can block atherosclerosis induced thrombosis. 

Myocardial Infarction

TP receptor activation causes a concentration-dependent increase in cardiomyocyte death while TP receptor antagonists inhibit cell death induced by U46629, a TxA2 mimetic (Touchberry et al, 2014). TP receptor agonism is known to regulate and active RhoA signaling which induces fibrosis through the activation of Rho-associated kinase pathway (Wikstrom et al, 2008). Overexpression of RhoA leads to dilated cardiomyopathy and heart failure, inducing sinus and atrioventricular nodal dysfunction, severe edema, increased cardiac fibrosis, atrial enlargement, and decreased fractional shortening (Sah et al, 1999). 

Additionally, PGD2/DP2 via Gαq stimulates intracellular calcium flux and activated m- calpain/caspase-12 cascade in cardiomyocytes, thereby inducing cardiomyocyte apoptosis (Zuo et al, 2018). Blockage of m-calpain prevented DP2-mediated cardiomyocyte apoptosis under ER stress by suppressing caspase-12 activity (Zuo et al, 2018). Thus, DP2 receptor antagonism with ramatroban may be beneficial in preventing cardiomyocyte apoptosis and fibrosis. 

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