1Medizinische Hochschule Hannover Kardiologie und Angiologie Hannover, Deutschland; 2Medizinische Hochschule Hannover Institut für Pathologie Hannover, Deutschland
Background: Pregnancy-associated volume overload and changes in the hormonal system induce cardiac hypertrophy. Mitochondrial motility, which is transduced by Ras Homolog Family Member T (Rhot) 1 and Rhot2, is critical for cardiac adaptations in the context of increased workload. However, the impact of Rhot1 and Rhot2 in the heart and on pregnancy-associated cardiac adaptions is currently not known.
Methods and results: We generated mice with cardiomyocyte-specific deletion of Rhot1 and Rhot2 that was induced at 8 weeks of age by a Tamoxifen-inducible Cre transgene (iRhot12KO). Motility of mitochondria isolated from iRhot12KO hearts was impaired by 57% (p=0.0015) as determined by the number of mobile mitochondria using an in vitro kinesin-1 single-molecule assay. iRhot12KO exhibited no baseline phenotype as assessed by transthoracic echocardiography, histological analysis, and mRNA expression of heart failure markers (Acta1, Nppa, and Nppb) relative to controls. To determine the impact of Rhot isoforms on pregnancy-associated cardiac adaptions, female iRhot12KO mice and wildtype controls were mated and cardiac tissue and function were analyzed after three to five consecutive pregnancies and nursing periods. Age-matched nulli para (NP) iRhot12KO and wildtype mice were used as controls. Heart weights were similarly increased in both genotypes post-birth and postpartum (PP) at the end of the nursing period compared to NP control mice. Contractile function (transthoracic echocardiography) and mRNA expression of heart failure markers were not different in iRhot12KO mice relative to NP and wildtype PP controls.
Conclusion: Mitochondrial motility, which is mediated by Rhot isoforms, is dispensable for contractile function in the adult heart. During pregnancy and postpartum, inducible cardiomyocyte-specific deficiency of Rhot1 and Rhot2 does not induce additional pathophysiological cardiac hypertrophy and pregnancy-associated heart failure.