Endoglin Selectively Modulates Transient Receptor Potential Channel Expression in Left and Right Heart Failure

Abstract Introduction Transient receptor potential (TRP) channels are broadly expressed cation channels that mediate diverse physiological stimuli and include canonical (TRPC), melastatin (TRPM) and vanilloid (TRPV) subtypes. Recent studies have implicated a role for TRPC6 channels as an important component of signaling via the cytokine, transforming growth factor beta 1 (TGFb1) in right (RV) or left ventricular (LV) failure. Endoglin is a transmembrane glycoprotein that promotes TRPC6 expression and TGFb1 activity. No studies have defined biventricular expression of all TRP channel family members in heart failure. Hypothesis We hypothesized that heart failure is associated with distinct patterns of TRP channel expression in the LV and RV. Methods Paired viable left (LV) and right (RV) ventricular free wall tissue was obtained from human subjects with end-stage heart failure (n=12) referred for cardiac transplantation or biventricular assist device implantation. Paired LV and RV samples from human subjects without heart failure served as controls (n=3). To explore a functional role for endoglin (Eng) as a regulator of TRP expression in response to RV or LV pressure overload, wild-type (Eng+/+) and Eng haploinsufficient (Eng+/−) mice were exposed to thoracic aortic (TAC) or pulmonary arterial (PAC) constriction for 8 weeks. Biventricular tissue was analyzed by real-time polymerase chain reaction. Results Compared to non-failing human LV and RV samples, mRNA levels of TRPC1, 3, 4, 6 and TRPV-2 were increased and TRPM2, 3, and 8 were decreased in failing LV and RV samples. TRPC1 and 6 levels were higher in failing RV compared to failing LV samples. After TAC, murine LV levels of TPRC1 and 6 were increased in both Eng +/+ and Eng +/− mice compared to sham controls. LV levels of TRPC4; TRPM3 and 7; TRPV2 and 4 were increased in Eng +/+, not Eng +/− mice after TAC. After PAC, all TRP channel family members were increased in the RV, but not LV, of Eng +/+ compared to sham controls. In contrast to Eng+/+, PAC did not increase RV or LV levels of TRP channels in Eng +/− mice. Conclusions This is the first study to demonstrate that TRP channels exhibit distinct profiles of expression in the LV and RV of patients with heart failure and in murine models of univentricular pressure overload. We further introduce that the TGFb1 co-receptor endoglin selectively regulates expression of multiple TRP channels in the setting of LV or RV pressure overload.