The transient receptor potential melastatin (TRPM) subfamily belongs to the TRP cation channels family. Since the first cloning of TRPM1 in 1989, tremendous progress has been made in identifying novel members of the TRPM subfamily and their functions. The TRPM subfamily is composed of eight members consisting of four six-transmembrane domain subunits, resulting in homomeric or heteromeric channels. From a structural point of view, based on the homology sequence of the coiled-coil in the C-terminus, the eight TRPM members are clustered into four groups: TRPM1/M3, M2/M8, M4/M5 and M6/M7. TRPM subfamily members have been involved in several physiological functions. However, they are also linked to diverse pathophysiological human processes. Alterations in the expression and function of TRPM subfamily ion channels might generate several human diseases including cardiovascular and neurodegenerative alterations, organ dysfunction, cancer and many other channelopathies. These effects position them as remarkable putative targets for novel diagnostic strategies, drug design and therapeutic approaches. Here, we review the current knowledge about the main characteristics of all members of the TRPM family, focusing on their actions in human diseases.

During systemic inflammation, reactive oxygen species (ROS) are generated in the bloodstream, producing large amounts of oxidized HDL (oxHDL). OxHDL loses the vascular protective features of native HDL, acquiring detrimental actions. Systemic inflammation promotes endothelial fibrosis, characterized by adhesion protein downregulation and fibrotic-specific gene upregulation, disrupting endothelial monolayer integrity. Severe systemic inflammatory conditions, as found in critically ill patients in the intensive care unit (ICU), exhibit endothelial hyperpermeability, hypotension, and organ hypoperfusion, promoting organ dysfunction and increased mortality. Because endothelial fibrosis disturbs the endothelium, it is proposed that it is the cellular and molecular origin of endothelial hyperpermeability and the subsequent deleterious consequences. However, whether oxHDL is involved in this process is unknown. The aim of this study was to investigate the fibrotic effect of oxHDL on the endothelium, to elucidate the underlying molecular and cellular mechanism, and to determine its effects on vascular permeability, blood pressure, and mortality. The results showed that oxHDL induces endothelial fibrosis through the LOX-1/NOX-2/ROS/NF-κB pathway, TGF-β secretion, and ALK-5/Smad activation. OxHDL-treated rats showed endothelial hyperpermeability, hypotension, and an enhanced risk of death and mortality, which was prevented using an ALK-5 inhibitor and antioxidant diet consumption. Additionally, the ICU patients showed fibrotic endothelial cells, and the resuscitation fluid volume administered correlated with the plasma oxHDL levels associated with an elevated risk of death and mortality. We conclude that oxHDL generates endothelial fibrosis, impacting blood pressure regulation and survival.