Abstract
Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, with prevalence continuing to rise. Historically, CVD was considered a male-dominant disease, and as a result, many treatments were developed using predominantly male subjects, overlooking female cardiac health. Arrhythmia, a common CVD complication characterised by disrupted cardiac electrical conduction, can either be mitigated or exacerbated by the signalling molecule nitric oxide (NO). Premenopausal women exhibit greater NO bioavailability due to oestrogen-enhanced expression, which is thought to provide a key cardioprotective mechanism. Emerging evidence suggests that differences in NO signalling contribute to sexual dimorphism in cardiac function.
One downstream target of NO implicated in this process is calcium/calmodulin-dependent protein kinase II delta (CaMKIIδ). Our group has identified that nitrosylation of CaMKIIδ at cysteine-273 (C273) inhibits kinase activity and reduces arrhythmia incidence. Preliminary data from our laboratory indicate sex-specific differences in arrhythmia susceptibility, with female C273S mutant mice exhibiting a higher arrhythmia incidence than males, potentially due to disruption of this nitrosylation site. However, the precise role of CaMKIIδ nitrosylation in regulating cardiac function, particularly arrhythmia, across sexes remains unclear.
Based upon this gap in understanding, this study aimed to determine how the loss of CaMKIIδ C273 nitrosylation influences cardiac function and arrhythmia risk in a sex-specific context. We hypothesised that female C273S mice would lose NO-mediated cardio protection, resulting in cardiac profiles more closely resembling those of males. In vivo electrocardiography was used to access cardiac electrical function in 12-week-old C273S mice compared with C57BL/6 controls, while echocardiography evaluated systolic and diastolic performance at baseline. Vaginal cytology was performed to determine oestrous cycle stage in female mice, allowing assessment of potential oestrogen-related effects on arrhythmia development.
Electrocardiographic analysis revealed no arrhythmic activity at baseline, however, significant differences in electrical conduction were noted between genotypes and sexes. Echocardiographic assessment identified significant differences in systolic function between genotypes and sexes; however, no diastolic phenotypes were altered. In both sets of data male C273S mice displayed a more altered phenotype, countering the studies hypothesis and implicating a potential alternate pathway for such a divergence. Oestrous cycle assessment revealed no significant associations between cycle stage and cardiac electrical and functional performance. Collectively, these findings demonstrate that the C273 residue of CaMKIIδ plays a baseline role in maintaining normal electrical conduction and systolic function, and that removal of this regulatory ‘brake’ promotes early pathological changes. Targeting this site may therefore represent a novel, sex-directed therapeutic strategy for arrhythmia management.