Liu Yamin, Atiq Amina, Peterson Anna, Moody Mikayla, Novin Ashkan, Deymier Alix C, Afzal Junaid
Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT 06032, USA.
Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, CA 94158, USA.
Metabolites. 2023 Apr 12;13(4):549. doi: 10.3390/metabo13040549.
Metabolic acidosis (MA) is a highly prevalent disorder in a significant proportion of the population, resulting from imbalance in blood pH homeostasis. The heart, being an organ with very low regenerative capacity and high metabolic activity, is vulnerable to chronic, although low-grade, MA. To systematically characterize the effect of low-grade MA on the heart, we treated male and female mice with NHCl supplementation for 2 weeks and analyzed their blood chemistry and transcriptomic signature of the heart tissue. The reduction of pH and plasma bicarbonate levels without an associated change in anion gap indicated a physiological manifestation of low-grade MA with minimal respiratory compensation. On transcriptomic analysis, we observed changes in cardiac-specific genes with significant gender-based differences due to MA. We found many genes contributing to dilated cardiomyopathy to be altered in males, more than in females, while cardiac contractility and Na/K/ATPase-Src signaling were affected in the opposite way. Our model presents a systems-level understanding of how the cardiovascular tissue is affected by MA. As low-grade MA is a common ailment with many dietary and pharmaceutical interventions, our work presents avenues to limit chronic cardiac damage and disease manifestation, as well as highlighting the sex differences in MA-induced cardiovascular damage.
代谢性酸中毒（MA）在相当一部分人群中是一种高度普遍的病症，由血液pH值稳态失衡引起。心脏作为一个再生能力极低且代谢活动高的器官，易受慢性（尽管程度较轻）MA的影响。为了系统地表征轻度MA对心脏的影响，我们用氯化铵补充剂处理雄性和雌性小鼠两周，并分析它们的血液化学指标和心脏组织的转录组特征。pH值和血浆碳酸氢盐水平降低而阴离子间隙无相关变化，表明存在轻度MA的生理表现且呼吸代偿最小。在转录组分析中，我们观察到由于MA导致的心脏特异性基因变化存在显著的性别差异。我们发现许多导致扩张型心肌病的基因在雄性中比在雌性中变化更大，而心脏收缩力和钠/钾/ATP酶 - Src信号传导受到相反的影响。我们的模型提供了对心血管组织如何受MA影响的系统层面的理解。由于轻度MA是一种常见疾病，有许多饮食和药物干预措施，我们的工作为限制慢性心脏损伤和疾病表现提供了途径，并突出了MA诱导的心血管损伤中的性别差异。
