Department of Pharmaceutical Sciences, Washington State University, PBS 423, 412 E. Spokane Falls Blvd, Spokane, WA 99202-2131, USA.
Cardiovasc Res. 2022 Jan 29;118(2):386-398. doi: 10.1093/cvr/cvab008.
Protein kinase A (PKA) is a central regulator of cardiac performance and morphology. Myocardial PKA activation is induced by a variety of hormones, neurotransmitters, and stress signals, most notably catecholamines secreted by the sympathetic nervous system. Catecholamines bind β-adrenergic receptors to stimulate cAMP-dependent PKA activation in cardiomyocytes. Elevated PKA activity enhances Ca2+ cycling and increases cardiac muscle contractility. Dynamic control of PKA is essential for cardiac homeostasis, as dysregulation of PKA signalling is associated with a broad range of heart diseases. Specifically, abnormal PKA activation or inactivation contributes to the pathogenesis of myocardial ischaemia, hypertrophy, heart failure, as well as diabetic, takotsubo, or anthracycline cardiomyopathies. PKA may also determine sex-dependent differences in contractile function and heart disease predisposition. Here, we describe the recent advances regarding the roles of PKA in cardiac physiology and pathology, highlighting previous study limitations and future research directions. Moreover, we discuss the therapeutic strategies and molecular mechanisms associated with cardiac PKA biology. In summary, PKA could serve as a promising drug target for cardioprotection. Depending on disease types and mechanisms, therapeutic intervention may require either inhibition or activation of PKA. Therefore, specific PKA inhibitors or activators may represent valuable drug candidates for the treatment of heart diseases.
蛋白激酶 A（PKA）是心脏功能和形态的核心调节因子。心肌 PKA 的激活是由多种激素、神经递质和应激信号诱导的，其中最主要的是交感神经系统分泌的儿茶酚胺。儿茶酚胺与β-肾上腺素能受体结合，刺激心肌细胞中 cAMP 依赖性 PKA 的激活。PKA 活性的升高增强了 Ca2+循环，增加了心肌的收缩力。PKA 的动态控制对于心脏的稳态至关重要，因为 PKA 信号转导的失调与广泛的心脏疾病有关。具体来说，PKA 的异常激活或失活导致心肌缺血、肥大、心力衰竭以及糖尿病性、心尖球囊样综合征或蒽环类心肌病的发病机制。PKA 也可能决定收缩功能和心脏病易感性的性别差异。在这里，我们描述了 PKA 在心脏生理学和病理学中的作用的最新进展，强调了以前研究的局限性和未来的研究方向。此外，我们还讨论了与心脏 PKA 生物学相关的治疗策略和分子机制。总之，PKA 可能成为心脏保护的有前途的药物靶点。根据疾病类型和机制，治疗干预可能需要抑制或激活 PKA。因此，特定的 PKA 抑制剂或激活剂可能代表治疗心脏病的有价值的药物候选物。
