Mitochondrial Calcium Uniporter Regulates Proliferative Signaling Pathway in Neonatal Cardiac Fibroblasts
Authors: O‐Uchi Jin , Jhun Bong Sook 
Published: June 2021

Early postnatal hearts adapt to the substantial increase in systolic pressure by increasing the thickness of the ventricular wall as well as its tensile strength, which is achieved mainly by an increase in the size of cardiomyocytes (CMs) (but not the number of CMs) as well as a two‐fold increase in the number of cardiac fibroblasts (CFs). Importantly, CFs can also exhibit hyperplasic phenotype under the pathophysiological condition in adulthood such as after the cardiac injury and/or during the repair in respond to various stimuli in vivo including angiotensin II (Ang‐II). Although Ang‐II‐mediated pathological CF proliferation in adult hearts has been extensively studied, the cellular mechanism for transient hyperplasic phenotype in neonatal CFs (NCFs) from early postnatal hearts has not been elucidated. In addition, several reports showed that CF proliferation may occur via enhanced production of reactive oxygen species (ROS), but the detailed molecular mechanism including the involvement of mitochondrial signaling pathway remains unclear both in adult CFs and NCFs. The purpose of this study is to test the involvement of mitochondrial signaling pathway including mitochondrial Ca2+ (mtCa2+) and the reactive oxygen species (ROS) generation for activating NCF proliferative pathway in NCFs. Uing the NCFs isolated from day 1–2‐old rat neonatal hearts, we found that Ang‐II stimulation induces Ca2+ release from the endoplasmic reticulum (ER), followed by mtCa2+ uptake via mtCa2+ uniporter (MCU) confirmed by live cell imaging with mitochondria matrix‐targeted Ca2+ biosensor, mtRCamp1h, under the confocal microscopes. Ang II stimulation also leads to mitochondrial fragmentation and increase in the mitochondrial superoxide (mSO) levels assessed by expressing mtGFP and loading mtSO‐sensitive dye MitoSox Red, respectively. Moreover, we found that Ang‐II stimulation activates proliferative pathway including ERK1/2‐p38 MAPK pathway, which was abolished by the pretreatment of a mitochondria‐targeted antioxidant, Mito‐TEMPO without affecting the profiles of Ang II‐induced ER Ca2+ release and mtCa2+ uptake. Finally, the overexpression of dominant‐negative MCU also blocked Ang II‐mediated activation of proliferative pathways concomitant with the inhibition of mtCa2+ uptake in response to Ang II. In conclusion, mtSO generation induced by mtCa2+ accumulation requires for the activation of Ang‐II–mediated proliferative pathway in NCFs, indicating that MCU and mtROS may have important roles for the development of early neonatal hearts. Elucidation of these mechanisms in NCFs will also facilitate the design of the novel therapy for cardiac fibrosis frequently observed in adult heart failure, where pathological high Ang II concentration, oxidative stress and CF proliferation co‐exist.

Support or Funding Information

J.O.‐U. was supported by NIH/NHLBI R01HL136757, NIH/NIGMS P30GM1114750, AHA 16SDG27260248, Rhode Island Foundation #20164376 Medical Research Grant, and American Physiological Society (APS) 2017 Shih‐Chun Wang Young Investigator Award. B.S.J was supported by AHA 8CDA34110091.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.