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.

Trpm2 enhances physiological bioenergetics and protects against pathological oxidative cardiac injury: Role of Pyk2 phosphorylation

“…Trpm2 expression is significantly reduced in human failing hearts when compared with nonfailing hearts(Morine et al, 2016) provides indirect support of the hypothesis that Trpm2 is cardiac protective. Thus Ca 2+ influx via Trpm2 channels in disease states can either be friend (decreased phagocyte NOS-mediated ROS production, maintained…”

Probenecid treatment improves outcomes in a novel mouse model of peripartum cardiomyopathy

“…These findings are still of course preliminary. Further, the generalizability of the TRPV2 findings to human population will require further study since even though our data in animals demonstrated increased TRPV2 expression in response to stress [47], some researchers have reported decreased TRPV2 expression in human subjects with heart failure [50], while others have found no difference [51].…”

TRPC Channels in Cardiac Plasticity

“…Compared with TRPC1 and TRPC4, there are not many reports regarding the function of TRPC5 in the heart. Moreover, reported expression of TRPC5 in the heart and its change during heart failure vary among studies [88][89][90]. Recently we demonstrated that TRPC5 has an anti-hypertrophic effect in cardiomyocytes [91].…”