Investigation of Temperature Sensitive Ion Channels in Platelets

There have been ample reports of life-threatening events due to the human body’s response to high temperatures, for example, stroke, heart failure, and (more importantly) hypercoagulability. A notable condition that leads to increases in core-body temperature is exertional heat stroke. This condition is characterized by hyperthermia and dysfunction of the nervous system as a result of intense physical activity, and is particularly observed in on-duty firefighters engaged in fire suppression efforts; often resulting in at least a 1°C rise in core-body temperature. Based on these considerations, understanding the impact and mechanism of heat-induced occlusive CVD/illness is paramount, not only for increasing public awareness of the negative health effects of hyperthermia, but also for developing prevention and therapeutic strategies for the associated diseases. Unfortunately, studies in this regard have been very limited and/or associated with limitations. Thus, a few in vitro studies have shown that increases in core-body temperature/heat can indeed modulate platelet function; however, these studies showed a destructive effect at 42°C and/or that platelets may lose their capacity to aggregate. In addition, 40°C hyperthermia was found to induce phosphatidylserine externalization, caspase-3 activation, and increase mitochondrial depolarization, leading to platelet apoptosis. It is important to note that the temperatures tested were not necessarily “real-life” and that, as stated before, platelets and other tissues are prone to cellular damage at such temperatures. Thus, we will investigate herein the effects of real-world increases in core-body temperatures in the context of platelets. These studies have the following two goals: investigating the effect of increases in core-body temperatures on platelet-mediated CVD as well as determining the mechanism by which this modulates platelet function. We will utilize a validated “hyperthermia” exposure animal model, a host of in vitro and in vivo (mouse) animal assays, and pharmacological agents that target thermosensitive ion channels (TSICs) known to be expressed in platelets. It is noteworthy that the TSICs identified in platelets primarily belong to the Transient Receptor Potential (TRP) channel family. Among these channels, TRPV4, a non-specific cation channel, is recognized for its role as a warm channel and may respond to temperatures ranging from 37 to 39 °C, in platelets. Additionally, TRPV4 has a symbiotic relationship with the chloride channel Ano1, which is also categorized as a TSIC. However, the temperature sensitivity as well as importance of the TRPV4/Ano1 axis for platelet homeostasis remains uncertain. Ultimately, our findings should provide valuable insight regarding the mechanistic impact of increases in core-body temperatures on platelets and related disorders, as well as inform prevention efforts and therapeutic approaches for managing occlusive-CVD mediated by hyperthermia. Project Number: 1R21ES038666-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Environmental Health Sciences (NIEHS) | Principal Investigator: Fadi Khasawneh (+1 co-PI) | Institution: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR, COLLEGE STATION, TX | Award Amount: $423,500 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 IVBH-P (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11353638