McNair Benjamin D, Yusifov Aykhan, Thornburg Joshua P, Hoopes Caleb R, Satyanarayana Sushumna B, Roy Tathagato, Gigley Jason P, Bruns Danielle R
Kinesiology and Health, University of Wyoming, Laramie, Wyoming, USA.
WWAMI Medical Education, University of Washington School of Medicine, Seattle, Washington, USA.
Aging Cell. 2025 Jan;24(1):e14339. doi: 10.1111/acel.14339. Epub 2024 Sep 19.
Aging is the primary risk factor for heart disease, the leading global cause of death. Right ventricular (RV) function predicts survival in several age-related clinical contexts, yet no therapies directly improve RV function, in large part due to a poor mechanistic understanding of RV aging and how it is distinct from the widely studied left ventricle (LV). To address this gap, we comprehensively quantified RV functional and morphological remodeling with age. We further aimed to identify molecular mechanisms of RV aging thus we performed RNAseq on RV and LV from male and female young (4 months) and aged (19-21 months) C57BL6 mice. Contrary to the concentric hypertrophic remodeling and diastolic dysfunction that occurs in the LV, the aging RV underwent eccentric remodeling with significant dilation and impaired systolic function. Transcriptomic data were also consistent with ventricle-specific aging, with few genes (13%) similarly shared between ventricles with aging. KEGG analysis identified shared aging genes in inflammatory and immune cell pathways that were confirmed by flow cytometry that demonstrated higher percent of GR1+ myeloid cells in both ventricles. Unique RV aging genes enriched in the biosynthesis of saturated fatty acids, PPAR signaling, and butanoate metabolism, and we identified putative novel RV-specific aging genes. Together, we suggest that the RV and LV are unique cardiac chambers that undergo distinct remodeling with age. These robust differences may explain why therapies designed from LV-based studies fail to improve RV function and suggest that future efforts emphasizing ventricular differences may elucidate new therapies for healthy cardiac aging.
衰老为心脏病的主要风险因素，而心脏病是全球主要死因。右心室（RV）功能可预测多种与年龄相关临床情况下的生存率，但尚无疗法能直接改善RV功能，很大程度上是因为对RV衰老及其与广泛研究的左心室（LV）的差异缺乏深入的机制理解。为填补这一空白，我们全面量化了RV随年龄增长的功能和形态重塑。我们进一步旨在确定RV衰老的分子机制，因此对雄性和雌性年轻（4个月）及老年（19 - 21个月）C57BL6小鼠的RV和LV进行了RNA测序。与LV发生的向心性肥厚重塑和舒张功能障碍相反，衰老的RV经历了离心性重塑，伴有显著扩张和收缩功能受损。转录组数据也与心室特异性衰老一致，随着年龄增长，心室间相似共享的基因很少（13%）。KEGG分析确定了炎症和免疫细胞途径中的共享衰老基因，流式细胞术证实了这一点，流式细胞术显示两个心室中GR1 + 髓样细胞的百分比更高。独特的RV衰老基因富集于饱和脂肪酸生物合成、PPAR信号传导和丁酸代谢中，并且我们确定了推测的新型RV特异性衰老基因。总之，我们认为RV和LV是独特的心腔，随年龄增长会经历不同的重塑。这些显著差异可能解释了基于LV研究设计的疗法为何无法改善RV功能，并表明未来强调心室差异的研究可能会阐明促进心脏健康衰老的新疗法。
