Reply to the commentary on “Blockade of thromboxane A2 signaling attenuates ethanol-induced myocardial inflammatory response in mice”

We appreciate the commentary by Sharp and Van (2024) on our recent publication regarding the effect of antagonizing thromboxane-prostanoid receptor (TP-R) in attenuating ethanol-induced myocardial inflammatory response in mice (Ai et al., 2024). In this commentary, Sharp and Van raised some concerns about our study design, clinical significance, and novelty of targeting TP-R as a therapeutic strategy for alcohol-associated cardiomyopathy (ACM). Some of the concerns and points made by Sharp and Van regarding our article are addressed below.

One of the concerns is that our study lacked cardiac function measurements. This is an important point, and we have acknowledged this limitation in the discussion and our study mainly focused on the molecular changes happening during early-cardiac injury. However, it is our intent to perform functional studies, and we are currently working on performing echocardiography to determine the effectiveness of SQ 29,548 (SQ) in altering cardiac function upon ethanol exposure. A study by Matyas et al. (2016) showed that the chronic plus one binge model used in our study exhibits markers of cardiac dysfunction including contractile dysfunction and impaired left ventricular relaxation. Therefore, further assessment of cardiac function in this model is likely to provide information regarding the effectiveness of SQ in improving ethanol-induced cardiac dysfunction.

It is also discussed that TP-R antagonists persist as a powerful research tool, yet they currently lack clinical utility. We respectfully disagree with this comment. In fact, TP-R antagonists are being used to manage asthma, arterial thrombosis, and peripheral artery disease in some Asian and European countries (Capra et al., 2014). Moreover, Picotamide, a combined inhibitor of thromboxane A2 (TXA2) synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease (Neri Serneri et al., 2004). Further, this drug improved renal hemodynamics and kidney function and favorably affects indices of cardiac performance in patients with severe congestive heart failure (Castellani et al., 2003). Ifetroban, a TP-R antagonist, has been recently approved by the FDA for the treatment of Duchenne muscular dystrophy. Moreover, other Phase 2 trials are ongoing to determine the effectiveness of Ifetroban against idiopathic pulmonary fibrosis and systemic sclerosis. Thus, targeting TP-R remains a promising approach to manage a number of ailments including cardiovascular disease.

It is argued that the adverse effects of aspirin, which inhibits cyclooxygenase (COX) 1 and downstream TXA2, limits the clinical utility of current TP-R-related pharmacotherapies. It should be pointed out that COX inhibitors and TP-R antagonists are different classes of compounds. COX inhibitors inhibit the formation of both prostaglandins and thromboxanes from arachidonic acid. While some prostaglandins are pro-inflammatory, some are involved in the resolution of inflammation. Because of this, prolonged use of these drugs leads to adverse side effects. On the other hand, agents blocking TP-R signaling are not likely to interfere with prostaglandin formation. Due to the difference in the mechanism of action, comparing TP-R inhibitors with COX1 inhibitors may not provide a good understanding of the clinical use of the TP-R antagonists.

There appears to be a concern about the novelty of our study. Although TP-R has been studied for its role in cardiovascular disease, its role in altering ethanol-induced cardiac injury remains unknown. The findings will be relevant to consider these drugs to treat alcohol-associated organ injury for which no established treatment option is available.

Sharp and Van have made other important points. For example, they have pointed out that mouse and humans exhibit variation in TP-R isoforms and therefore more relevant preclinical testing should be carried out to produce more meaningful observations. We completely agree with the authors' point. Humans express two isoforms of TP-R, TPα and TPβ, having a difference in the C-terminal region (Nakahata, 2008). Rodents only express TPα, which is similar to human TPα. Evidence suggests that these two isoforms couple with different G proteins, leading to different downstream effects (Nakahata, 2008). More studies are needed to better determine the role of TP-R isoforms in altering the development of human pathologies. Next, they have suggested that in addition to the treatment of alcohol-induced inflammation and cardiomyopathy, successful implementation of TP-R antagonism may lead to a new therapeutic strategy for modern day cardiovascular-related diseases, including hypertension, obesity, diabetes, and heart failure. In fact, markers of TP-R signaling have been reported to be increased in human subjects with obesity and/or insulin resistance. Moreover, we recently reported that blocking TP-R attenuates lipopolysaccharide and free fatty acid-induced inflammatory response in human peripheral blood mononuclear cells (Rajamanickam et al., 2024). Future translational studies in human subjects will provide important information regarding role of TP-R as a therapeutic target for a number of cardiovascular diseases and its comorbidities. We thank the authors for this important discussion and for providing us with an opportunity to clarify these issues to the scientific community.

This study was supported by the National Institute on Alcohol Abuse and Alcoholism (grant/award number: P50AA030407-5130) and American Heart Association (grant/award number: 23PRE1019901).

The authors declare no conflict of interest.