Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Korea.
Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, Korea.
PLoS One. 2022 Jul 21;17(7):e0267938. doi: 10.1371/journal.pone.0267938. eCollection 2022.
Hypertension or hypotension prevails as a comorbidity in patients with heart failure (HF). Although blood pressure (BP) is an important factor in managing the mortality of HF, the molecular mechanisms of changes in BP have not been clearly understood in cases of HF. We and others have demonstrated that a loss in PRDM16 causes hypertrophic cardiomyopathy, leading to HF. We aimed to determine whether BP is altered in mice that experience cardiac loss of Prdm16 and identify the underlying mechanism of BP-associated changes. BP decreased significantly only in female mice with a cardiac-null mutation of Prdm16 compared with controls, by an invasive protocol under anesthesia and by telemetric method during conscious, unrestrained status. Mice with a cardiac loss of Prdm16 had higher heart-to-body weight ratios and upregulated atrial natriuretic peptide, suggesting cardiac hypertrophy. Plasma aldosterone-to-renin activity ratios and plasma sodium levels decreased in Prdm16-deficient mice versus control. By RNA-seq and in subsequent functional analyses, Prdm16-null hearts were enriched in factors that regulate BP, including Adra1a, Nos1, Nppa, and Nppb. The inhibition of nitric oxide synthase 1 (NOS1) reverted the decrease in BP in cardiac-specific Prdm16 knockout mice. Mice with cardiac deficiency of Prdm16 present with hypotension and cardiac hypertrophy. Further, our findings suggest that the increased expression of NOS1 causes hypotension in mice with a cardiac-null mutation of Prdm16. These results provide novel insights into the molecular mechanisms of hypotension in subjects with HF and contribute to our understanding of how hypotension develops in patients with HF.
高血压或低血压是心力衰竭（HF）患者的常见合并症。虽然血压（BP）是管理 HF 死亡率的重要因素，但 HF 病例中 BP 变化的分子机制尚不清楚。我们和其他人已经证明，PRDM16 的缺失会导致肥厚型心肌病，从而导致 HF。我们旨在确定在经历心脏 PRDM16 缺失的小鼠中 BP 是否发生变化，并确定与 BP 相关变化的潜在机制。与对照组相比，仅在心脏缺失 Prdm16 的雌性小鼠中，通过麻醉下的侵入性方案和清醒、不受限制状态下的遥测方法，BP 显著降低。心脏缺失 Prdm16 的小鼠的心脏重量与体重比升高，心房利钠肽上调，提示心肌肥大。与对照组相比，Prdm16 缺陷小鼠的血浆醛固酮与肾素活性比值和血浆钠水平降低。通过 RNA-seq 和随后的功能分析，Prdm16 缺失的心脏富含调节 BP 的因子，包括 Adra1a、Nos1、Nppa 和 Nppb。一氧化氮合酶 1（NOS1）的抑制可逆转心脏特异性 Prdm16 敲除小鼠中 BP 的降低。心脏缺失 Prdm16 的小鼠表现出低血压和心肌肥大。此外，我们的发现表明，NOS1 的表达增加导致心脏缺失 Prdm16 的小鼠出现低血压。这些结果为 HF 患者中低血压的分子机制提供了新的见解，并有助于我们了解 HF 患者中低血压的发展机制。
