Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis.

Pathological cardiac remodeling, characterized by cardiac hypertrophy and fibrosis, is a pathological feature of many cardiac disorders that leads to heart failure and cardiac arrest. Vinpocetine, a derivative of the alkaloid vincamine, has been used for enhancing cerebral blood flow to treat cognitive impairment. However, its role in pathological cardiac remodeling remains unknown. The aim of this study is to examine the effect of vinpocetine on pathological cardiac remodeling induced by chronic stimulation with angiotensin II (Ang II). Mice received Ang II infusion via osmotic pumps in the presence of vehicle or vinpocetine. Cardiac hypertrophy and fibrosis were assessed by morphological, histological, and biochemical analyses. Mechanistic studies were carried out in vitro with isolated mouse adult cardiac myocytes and fibroblasts. We showed that chronic Ang II infusion caused cardiac hypertrophy and fibrosis, which were all significantly attenuated by systemic administration of vinpocetine. In isolated adult mouse cardiomyocytes, vinpocetine suppressed Ang II-stimulated myocyte hypertrophic growth. In cultured cardiac fibroblasts, vinpocetine suppressed TGFβ-induced fibroblast activation and matrix gene expression, consistent with its effect in attenuating cardiac fibrosis. The effects of vinpocetine on cardiac myocyte hypertrophy and fibroblast activation are likely mediated by targeting cyclic nucleotide phosphodiesterase 1 (PDE1). Our results reveal a novel protective effect of vinpocetine in attenuating pathological cardiac remodeling through suppressing cardiac myocyte hypertrophic growth and fibroblast activation and fibrotic gene expression. These studies may also shed light on developing novel therapeutic agents for antagonizing pathological cardiac remodeling.

病理性心脏重构以心脏肥大和纤维化为特征，是许多心脏疾病的病理特征，会导致心力衰竭和心脏骤停。长春西汀是生物碱长春胺的衍生物，已被用于增加脑血流量以治疗认知障碍。然而，其在病理性心脏重构中的作用仍不清楚。本研究的目的是检验长春西汀对血管紧张素II（Ang II）慢性刺激诱导的病理性心脏重构的影响。 在给予溶媒或长春西汀的情况下，小鼠通过渗透泵接受Ang II输注。通过形态学、组织学和生物化学分析评估心脏肥大和纤维化。利用分离的小鼠成年心肌细胞和成纤维细胞进行了机制研究。 我们发现，慢性Ang II输注导致心脏肥大和纤维化，而全身给予长春西汀可显著减轻这些症状。在分离的成年小鼠心肌细胞中，长春西汀抑制了Ang II刺激的心肌细胞肥大生长。在培养的心脏成纤维细胞中，长春西汀抑制了转化生长因子β（TGFβ）诱导的成纤维细胞活化和基质基因表达，这与其减轻心脏纤维化的作用一致。长春西汀对心肌细胞肥大和成纤维细胞活化的作用可能是通过靶向环核苷酸磷酸二酯酶1（PDE1）介导的。 我们的研究结果揭示了长春西汀通过抑制心肌细胞肥大生长、成纤维细胞活化和纤维化基因表达在减轻病理性心脏重构方面的一种新的保护作用。这些研究也可能为开发拮抗病理性心脏重构的新型治疗药物提供思路。