van Marion Denise Ms, Hu Xu, Zhang Deli, Hoogstra-Berends Femke, Seerden Jean-Paul G, Loen Lizette, Heeres Andre, Steen Herman, Henning Robert H, Brundel Bianca Jjm
Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands,
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands.
Drug Des Devel Ther. 2019 Jan 18;13:345-364. doi: 10.2147/DDDT.S176924. eCollection 2019.
The heat shock protein (HSP) inducer, geranylgeranylacetone (GGA), was previously found to protect against atrial fibrillation (AF) remodeling in experimental model systems. Clinical application of GGA in AF is limited, due to low systemic concentrations owing to the hydrophobic character of GGA.
To identify novel HSP-inducing compounds, with improved physicochemical properties, that prevent contractile dysfunction in experimental model systems for AF.
Eighty-one GGA-derivatives were synthesized and explored for their HSP-inducing properties by assessment of HSP expression in HL-1 cardiomyocytes pretreated with or without a mild heat shock (HS), followed by incubation with 10 µM GGA or GGA-derivative. Subsequently, the most potent HSP-inducers were tested for preservation of calcium transient (CaT) amplitudes or heart wall contraction in pretreated tachypaced HL-1 cardiomyocytes (with or without HSPB1 siRNA) and , respectively. Finally, CaT recovery in tachypaced HL-1 cardiomyocytes posttreated with GGA or protective GGA-derivatives was determined.
Thirty GGA-derivatives significantly induced HSPA1A expression after HS, and seven showed exceeding HSPA1A expression compared to GGA. GGA and nine GGA-derivatives protected significantly from tachypacing (TP)-induced CaT loss, which was abrogated by HSPB1 suppression. GGA and four potent GGA-derivatives protected against heart wall dysfunction after TP compared to non-paced control . Of these compounds, GGA and three GGA-derivatives induced a significant restoration from CaT loss after TP of HL-1 cardiomyocytes.
We identified novel GGA-derivatives with improved physicochemical properties compared to GGA. GGA-derivatives, particularly GGA-59, boost HSP expression resulting in prevention and restoration from TP-induced remodeling, substantiating their role as novel therapeutics in clinical AF.
热休克蛋白（HSP）诱导剂香叶基香叶基丙酮（GGA）先前在实验模型系统中被发现可预防心房颤动（AF）重塑。由于GGA的疏水性导致全身浓度较低，GGA在AF中的临床应用受到限制。
鉴定具有改善的物理化学性质的新型HSP诱导化合物，这些化合物可预防AF实验模型系统中的收缩功能障碍。
合成了81种GGA衍生物，并通过评估在有或没有轻度热休克（HS）预处理的HL-1心肌细胞中的HSP表达来探索它们的HSP诱导特性，随后用10μM GGA或GGA衍生物孵育。随后，测试了最有效的HSP诱导剂对预处理的快速起搏HL-1心肌细胞（有或没有HSPB1 siRNA）中钙瞬变（CaT）幅度的保留或心脏壁收缩的影响。最后，测定了用GGA或保护性GGA衍生物处理后的快速起搏HL-1心肌细胞中的CaT恢复情况。
30种GGA衍生物在HS后显著诱导HSPA1A表达，7种与GGA相比显示出超过HSPA1A的表达。GGA和9种GGA衍生物可显著保护免受快速起搏（TP）诱导的CaT损失，HSPB1抑制可消除这种损失。与非起搏对照相比，GGA和4种有效的GGA衍生物可预防TP后的心脏壁功能障碍。在这些化合物中，GGA和3种GGA衍生物可诱导HL-1心肌细胞TP后CaT损失的显著恢复。
我们鉴定出了与GGA相比具有改善的物理化学性质的新型GGA衍生物。GGA衍生物，特别是GGA-59，可促进HSP表达，从而预防和恢复TP诱导的重塑，证实了它们作为临床AF新型治疗药物的作用。
