Voelker Taylor L, Westhoff Maartje, Del Villar Silvia G, Thai Phung N, Chiamvimonvat Nipavan, Nieves-Cintrón Madeline, Dickson Eamonn J, Dixon Rose E
Dept. of Physiology and Membrane Biology, University of California, Davis, CA, 95616, USA; present address: Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
Dept. of Physiology and Membrane Biology, University of California, Davis, CA, 95616, USA.
bioRxiv. 2025 Feb 27:2025.02.23.639781. doi: 10.1101/2025.02.23.639781.
Contractile dysfunction, hypertrophy, and cell death during heart failure are linked to altered Ca handling, and elevated levels of the hormone angiotensin II (AngII), which signals through G-coupled AT receptors, initiating hydrolysis of PIP. Chronic elevation of AngII contributes to cardiac pathology, but the mechanisms linking sustained AngII signaling to heart dysfunction remain incompletely understood. Here, we demonstrate that chronic AngII exposure profoundly disrupts cardiac phosphoinositide homeostasis, triggering a cascade of cellular adaptations that ultimately impair cardiac function. Using AngII infusion combined with phospholipid mass spectrometry, super-resolution microscopy, and functional analyses, we show that sustained AngII signaling reduces PI(4,5)P levels and triggers extensive redistribution of Ca1.2 channels from t-tubules to various endosomal compartments. Despite this t-tubular channel loss, enhanced sympathetic drive maintains calcium currents and transients through increased channel phosphorylation via PKA and CaMKII pathways. However, this compensation proves insufficient as cardiac function progressively declines, marked by pathological hypertrophy, t-tubule disruption, and diastolic dysfunction. Notably, we identify depletion of PI(3,4,5)P as a critical mediator of AngII-induced cardiac pathology. While preservation of PI(3,4,5)P levels through PTEN inhibition did not prevent cellular remodeling or calcium handling changes, it protected against cardiac dysfunction, suggesting effects primarily through reduction of fibrosis. These findings reveal a complex interplay between phosphoinositide signaling, ion channel trafficking, and sympathetic activation in AngII-induced cardiac pathology. Moreover, they establish maintenance of PI(3,4,5)P as a promising therapeutic strategy for hypertensive heart disease and as a potential protective adjunct therapy during clinical AngII administration.
心力衰竭期间的收缩功能障碍、心肌肥大和细胞死亡与钙处理改变以及激素血管紧张素 II（AngII）水平升高有关，AngII 通过 G 偶联的 AT 受体发出信号，启动磷脂酰肌醇-4,5-二磷酸（PIP）的水解。AngII 的长期升高会导致心脏病变，但将持续的 AngII 信号传导与心脏功能障碍联系起来的机制仍未完全清楚。在这里，我们证明长期暴露于 AngII 会严重破坏心脏磷酸肌醇稳态，引发一系列细胞适应性变化，最终损害心脏功能。通过将 AngII 输注与磷脂质谱分析、超分辨率显微镜和功能分析相结合，我们发现持续的 AngII 信号传导会降低磷脂酰肌醇-4,5-二磷酸（PI(4,5)P）水平，并触发 L 型钙通道（Ca1.2 通道）从横管向各种内体区室的广泛重新分布。尽管横管通道丢失，但增强的交感神经驱动通过蛋白激酶 A（PKA）和钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）途径增加通道磷酸化，从而维持钙电流和钙瞬变。然而，这种代偿被证明是不足的，因为心脏功能逐渐下降，表现为病理性肥大、横管破坏和舒张功能障碍。值得注意的是，我们确定磷脂酰肌醇-3,4,5-三磷酸（PI(3,4,5)P）的消耗是 AngII 诱导的心脏病变的关键介质。虽然通过抑制磷酸酶和张力蛋白同源物（PTEN）来维持 PI(3,4,5)P 水平并不能防止细胞重塑或钙处理变化，但它可以预防心脏功能障碍，表明主要通过减少纤维化发挥作用。这些发现揭示了磷酸肌醇信号传导、离子通道转运和交感神经激活在 AngII 诱导的心脏病变中的复杂相互作用。此外，它们确立了维持 PI(3,4,5)P 作为高血压性心脏病的一种有前景的治疗策略，以及在临床应用 AngII 期间作为一种潜在的保护性辅助治疗方法。
