Kaur Satinder, Bhatti Gurjit Kaur, Khullar Naina, Singh Sidhu Inderpal, Navik Umashanker, Bhatti Jasvinder Singh
Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, 151401, India.
Department of Medical Lab Technology, UIAHS, Chandigarh University, Mohali, India.
Mol Biol Rep. 2025 Sep 16;52(1):907. doi: 10.1007/s11033-025-10974-6.
Calcium (Ca²⁺), a fundamental intracellular second messenger, plays a pivotal role in cardiovascular physiology and pathology. While tightly regulated under normal conditions, Ca²⁺ homeostasis becomes profoundly dysregulated during myocardial infarction (MI), heart failure, ischemia-reperfusion injury, cardiac hypertrophy, and atherosclerosis, resulting in pathological signaling, organellar stress, and cardiomyocyte death. This review presents a comprehensive exploration of how intracellular Ca²⁺ orchestrates excitation-contraction coupling, mitochondrial energetics, sarcoplasmic reticulum (SR) buffering, and lysosomal signaling, while simultaneously modulating apoptosis, necrosis, pyroptosis, ferroptosis, and Clockophagy. We highlight the role of Ca²⁺ in the pathogenesis of atherosclerosis, vascular calcification, endothelial dysfunction, platelet activation, and fibroblast trans differentiation. In particular, we delineate how Ca²⁺ excitotoxicity extends across a range of organelles including mitochondria, the sarcoplasmic reticulum (SR), and lysosomes to mediate inter-organellar communication. This organellar communication, facilitated by Ca²⁺ signaling, drives the interplay of cardiac cell death mechanisms that culminate in cardiac tissue destruction. The involvement of TRPC channels in lysosome-SR-mitochondria crosstalk warrants further investigation to enable targeting of specific TRPC isoforms based on the type of cardiovascular disorder. Therapeutics targeting mitochondria-associated membranes (MAMs) and lysosomes simultaneously may offer a comprehensive and effective strategy for the treatment of cardiovascular disease.
钙（Ca²⁺）作为一种重要的细胞内第二信使，在心血管生理和病理过程中发挥着关键作用。在正常情况下，Ca²⁺受到严格调控，但在心肌梗死（MI）、心力衰竭、缺血再灌注损伤、心脏肥大和动脉粥样硬化期间，Ca²⁺稳态会严重失调，导致病理信号传导、细胞器应激和心肌细胞死亡。本综述全面探讨了细胞内Ca²⁺如何协调兴奋 - 收缩偶联、线粒体能量代谢、肌浆网（SR）缓冲和溶酶体信号传导，同时调节细胞凋亡、坏死、焦亡、铁死亡和自噬性溶酶体降解。我们强调了Ca²⁺在动脉粥样硬化、血管钙化、内皮功能障碍、血小板活化和成纤维细胞转分化发病机制中的作用。特别是，我们阐述了Ca²⁺兴奋性毒性如何扩展到包括线粒体、肌浆网（SR）和溶酶体在内的一系列细胞器，以介导细胞器间的通讯。这种由Ca²⁺信号传导促进的细胞器间通讯驱动了最终导致心脏组织破坏的心脏细胞死亡机制的相互作用。TRPC通道在溶酶体 - SR - 线粒体串扰中的作用值得进一步研究，以便根据心血管疾病的类型靶向特定的TRPC亚型。同时靶向线粒体相关膜（MAMs）和溶酶体的治疗方法可能为心血管疾病的治疗提供一种全面而有效的策略。
