OpiCa1 reduces inflammation and ROS levels counteracting heat stress-induced cardiac injury.

Heat stress exacerbates heart disease by increasing myocardial workload, and long-term exposure to high temperatures elevates cardiovascular risks. As a natural cell-penetrating peptide, OpiCa1 can rapidly bind to ryanodine receptors (RyRs), inducing a semi-open conformation and triggering calcium release. We explored OpiCa1's protective role against heat stress at 42 °C using cell viability assays, transcriptomics, and whole animal studies. Experiments showed that OpiCa1 treatment in heat-stressed H9C2 cells significantly reduced ROS, apoptosis, and inflammatory factors while increasing cell survival. OpiCa1 binds to RyRs, inducing a subconductive state and consequently restoring mitochondrial calcium homeostasis. It inhibits FOS-mediated apoptosis via modulation of the Bax/Bcl-2 ratio and suppresses inflammatory responses by regulating MAPK and PI3K signaling pathways. In heat-stressed mice, OpiCa1 significantly mitigated cardiac injury, reduced the expression levels of IL-1α and IL-6, and improved tissue integrity. Our findings reveal OpiCa1's dual function in mitigating oxidative stress and inflammation via critical apoptotic and signaling pathways, thereby presenting a promising therapeutic approach for heat-related cardiovascular disorders.