Humans are ubiquitously exposed to crotonaldehyde (CRA) endogenously and exogenously. Deeper knowledge of the pharmacological and toxicological characteristics and the mechanisms of CRA on vasculature is urgently needed for prevention of its harmfulness. The effects of acute and prolonged exposure to CRA were studied in rat isolated arteries and arterial smooth muscle cells (ASMCs). Instant exposure to CRA (1-300 μM) concentration-dependently declined the tension of pre-constricted arteries with an irreversible depression on the contractility. Prolonged exposure of rat coronary arteries (RCAs) to CRA concentration- and time-dependently depressed the arterial contractile responsiveness to various vasoconstrictors including depolarization, U46619, serotonin and Bay K8644 (an agonist of voltage-gated Ca²⁺ channels (VGCCs)). In fresh RCA ASMCs, CRA abated depolarization-induced elevation of intracellular Ca²⁺ ([Ca²⁺]_i). Electrophysiological study revealed that acute exposure to CRA depressed the functions of Ca²⁺-activated Cl^- channels (CaCCs), voltage-gated K⁺ (Kv) channels and inward rectifier K⁺ (Kir) channels in RCA ASMCs. Prolonged exposure of RCAs to CRA reduced the expressions of these ion channels in RCA ASMCs, disordered tissue frames, injured arterial cells, and increased autophagosomes in both ASMCs and endothelial cells. In rat aortic smooth muscle cells (A7r5), CRA exposure decreased the cell viability, elevated the intracellular levels of reactive oxygen species, reduced the mitochondrial membrane potential, and enhanced autophagy. Taken together, the present study for the first time portrays a clearer panoramic outline of the vascular effects and the mechanisms of CRA on arteries, demonstrates that CRA impairs arterial contractility, depresses VGCCs, CaCCs, Kv channels and Kir channels, reduces cell viability, and destroys the arterial histiocytes, and suggests that excessive oxidative stress, mitochondrial dysfunction and autophagy underlie these vascular damages. These findings are significant for the comprehensive evaluation of the vicious effects of CRA on arteries and suggest potential preventive strategies.

Statins are well-tolerated and widely available lipid-lowering medications with neuroprotective effects against traumatic brain injury (TBI). However, whether delayed statin therapy starting in the subacute phase promotes recovery after TBI is unknown. Elongation of the very long-chain fatty acid protein 1 (ELOVL1) is involved in astrocyte-mediated neurotoxicity, but its role in TBI and the relationship between ELOVL1 and statins are unclear. We hypothesized that delayed simvastatin treatment promotes neurological functional recovery after TBI by regulating the ELOVL1-mediated production of very long-chain fatty acids (VLCFAs). ICR male mice received daily intragastric administration of 1, 2 or 5 mg/kg simvastatin on Days 1-14, 3-14, 5-14, or 7-14 after cryogenic TBI (cTBI). The results showed that simvastatin promoted motor functional recovery in a dose-dependent manner, with a wide therapeutic window of at least 7 days postinjury. Meanwhile, simvastatin inhibited astrocyte and microglial overactivation and glial scar formation, and increased total dendritic length, neuronal complexity and spine density on day 14 after cTBI. The up-regulation of ELOVL1 expression and saturated VLCFAs concentrations in the cortex surrounding the lesion caused by cTBI was inhibited by simvastatin, which was related to the inhibition of the mTOR signaling. Overexpression of ELOVL1 in astrocytes surrounding the lesion using HBAAV2/9-GFAP-m-ELOVL1-3xFlag-EGFP partially attenuated the benefits of simvastatin. These results showed that delayed simvastatin treatment promoted functional recovery and brain tissue repair after TBI through the downregulation of ELOVL1 expression by inhibiting mTOR signaling. Astrocytic ELOVL1 may be a potential target for rehabilitation after TBI.