biostudies-literatureAmirrad FNHLBI NIH HHSU.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood InstituteU.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)2422https://www.ebi.ac.uk/biostudies/studies/S-EPMC11897200biostudies-literatureUnknown16(1)Progesterone receptors are classified into nuclear and membrane-bound receptor families. Previous unbiased proteomic studies indicate a potential association between cardiac diseases and the progesterone receptor membrane-bound component-2 (PGRMC2); however, the role of PGRMC2 in the heart remains unknown. In this study, we use a heart-specific knockout (KO) mouse model (MyH6•Pgrmc2^flox/flox) in which the Pgrmc2 gene was selectively deleted in cardiomyocytes. Here we show that PGRMC2 serves as a mediator of steroid hormones for rapid calcium signaling in cardiomyocytes to maintain cardiac contraction, sufficient stroke volume, and adequate cardiac output by regulating the cardiac pressure-volume relationship. The KO hearts from male and female mice exhibit an impairment in pressNature communicationsPGRMC2 is a pressure-volume regulator critical for myocardial responses to stress in mice.PMC11897200R01 HL147311HL131577Pru JKLa VOhadi SAlbotaif MShamloo KNauli SMMohieldin AMAmirrad FWebster SfalsePGRMC2 is a pressure-volume regulator critical for myocardial responses to stress in mice.Progesterone receptors are classified into nuclear and membrane-bound receptor families. Previous unbiased proteomic studies indicate a potential association between cardiac diseases and the progesterone receptor membrane-bound component-2 (PGRMC2); however, the role of PGRMC2 in the heart remains unknown. In this study, we use a heart-specific knockout (KO) mouse model (MyH6•Pgrmc2^flox/flox) in which the Pgrmc2 gene was selectively deleted in cardiomyocytes. Here we show that PGRMC2 serves as a mediator of steroid hormones for rapid calcium signaling in cardiomyocytes to maintain cardiac contraction, sufficient stroke volume, and adequate cardiac output by regulating the cardiac pressure-volume relationship. The KO hearts from male and female mice exhibit an impairment in press2025-01-01T00:00:00Z2025 Mar2026-05-29T19:11:01.501Z2025-04-04T01:28:22.541ZS-EPMC118972004006918010.1038/s41467-025-57707-8