Utilizing genetically engineered animals with global inactivation of ERα non-nuclear signalling, we recently reported the role of ERα non-nuclear signalling in heart failure, wherein ERα non-nuclear signalling contributes to myocardial PKG activity and cardiac remodelling in female, but not in male, animals.26 This study, however, did not explore the tissue-specific role in cardiac protection or its mechanism by ERα non-nuclear signalling. The gene discussed is PRKG1; the disease is heart failure.