Activation of Liver X Receptors by GW3965 attenuated DOCA-salt hypertension-induced cardiac functional and structural changes. Increased blood pressure (hypertension) is linked to adverse structural and functional remodeling of the heart that may develop into heart failure. Drugs that target these adverse cardiac remodeling events may prove to be beneficial beyond reducing blood pressure. In the August 2019 issue, Bal et al. report that a liver X receptor (LXR) agonist GW3965 improved cardiac function with increased blood pressure and lessened cardiac remodeling as evidenced by markers of inflammation, fibrosis, and ER stress. Notably, GW3965 did not fully normalize increased systolic blood pressure, nor was cardiac hypertrophy prevented by their treatment protocol. Activation of LXRs, which are nuclear hormone receptors, was previously linked to cardioprotection from ischemia-reperfusion injury and diabetes, and LXR activators have recently gained interest as potential therapies for heart failure. The study by Bal et al. is the first to report the benefit of LXR activation on cardiac changes induced by hypertension. Their preclinical model was the DOCA-salt + uni-nephrectomy rat. However, as will be discussed in an upcoming editorial, DOCA may exert direct remodeling actions on the heart through activation of the mineralocorticoid receptor by its metabolite DOC (deoxycorticosterone). Thus, further studies using other models of hypertension are warranted.
