Table 2.

Effect of catalpol on cardiovascular diseases in vivo.

Animal models		Dose and duration		Effects	Refs.
Atherosclerosis	Female ApoE−/− mice were fed with a high-fat diets and were underwent ovariectomy	20 mg/kg/day, i.g. 90 days		Reduced atherosclerotic lesions; improved serum lipid profiles (e.g., decrease of serum TG, TC, and LDL-C levels and increase of serum HDL-C levels); inhibited inflammatory response and oxidative stress; attenuated M1 macrophage markers (IL-12, CD86, and iNOS) and increased M2 macrophage markers (FIZZ1, CD206, and Arg-1); promoted the ERα expressions.	[46]
Atherosclerosis	Male New Zealand White rabbits were fed with high-cholesterol diets	5 mg/kg/day, i.g. 12 weeks		Attenuated atherosclerotic lesions; improved serum lipid profiles (e.g., decrease of serum TG, TC, and LDL-C levels and increase of serum HDL-C levels); reduced serum TNF-α, IL-6, MCP-1, sVCAM-1, and sICAM-1 levels, as well as the expression of MCP-1, VCAM-1, TNF-α, iNOS, MM-9, and NF-κB-p65 in the aortic arch; reduced lipid peroxidation levels, while elevated antioxidant capacity.	[47]
Atherosclerosis	Male LDLr−/− mice were fed high-fat diets (MD12017)	100 and 200 mg/kg/day, i.g. 16 weeks		Inhibited atherosclerotic lesion development and improved lipid profiles; increased SOD and GSH content, and inhibited MDA and LDH content; inhibited Nox2 and Nox4 expression and ROS accumulation; inhibited DNA oxidative damage and cell apoptosis; relieved cellular senescence and telomere dysfunction; activated the PGC-1α/TERT pathway.	[48]
Atherosclerosis	Male New Zealand White rabbits were injected intravenously with alloxan monohydrate (100 mg/kg) and were fed with hyperlipidemic diets	5 mg/kg/day, i.g. 12 weeks		Ameliorated diabetic atherosclerosis, as well as inhibited neointimal hyperplasia and macrophages recruitment; enhanced the activities of SOD, GSH-Px, and increased the plasma levels of total antioxidant status, meanwhile reduced the levels of MDA, protein carbonyl groups, and advanced glycation end product; reduced circulating levels of TNF-α, MCP-1, and VCAM-1; decreased TGF-β1 and collagen IV expressions in the vessels.	[49]
Atherosclerosis	Male Wistar rats were intraperitoneally injected with d-galactose (100 mg/kg/day)	5 and 10 mg/kg/day, i.p. 12 weeks		Improved the pathological damages of aortic vascular endothelial cells; inhibited cell apoptosis (e.g., downregulation of Bax and caspase-3 expression and reduction of Bcl-2 expression and Bcl-2/Bax ratio).	[50]
Atherosclerosis	Male Wistar rats were fed with high-fat diets and were injected intraperitoneally with STZ (30 mg/kg)	10, 50, and 100 mg/kg/day, i.g. 6 weeks		Attenuated endothelial damage of thoracic aorta; decreased 8-iso-PGF2α levels in serum, ROS levels, and expression of Nox4 and p22 phox in thoracic aorta; elevated serum NO and SOD levels.	[51]
Atherosclerosis	Male Wistar rats were injected intraperitoneally with STZ (90 mg/kg)	5 mg/kg/day, i.g. 2 weeks		Downregulated MCP-1 expression in carotid arteries; ameliorated neointimal hyperplasia.	[52]
Cerebral vascular diseases	Male Sprague-Dawley rats were subjected to pMCAO via electrocoagulation	5 mg/kg/day, i.p. 7 days		Improved the neuroethology deficit, increased the CBF of infarcted brain and upregulated EPO and EPOR; enhanced stroke-induced STAT3 activation and subsequently restored STAT3 activity through the recovery of STAT3 binding to VEGF; reversed the effect of AG490 on STAT3 activation and nuclear translocation, restored the transcriptional activity of the VEGF promoter by recruiting STAT3 to the VEGF promoter, improved VEGF expression, increased angiogenesis, reduced the difference in CBF between the infarcted and intact brain, and ameliorated the neuroethology behaviors after stroke.	[53]
Cerebral vascular diseases	Male Sprague-Dawley rats were subjected to MCAO via electrocoagulation	2.5, 5.0, and 10.0 mg/kg/day, i.v. 14 days		Improved neurological deficits and reduced the infarct volume; improved histological morphology and protected the vascular structure in the vicinity of the infarcted area; promoted angiogenesis and enhanced vessel density in the vicinity of the infarcted area; activated the HIF-1α/VEGF pathway in the brains.	[54]
Cerebral vascular diseases	Male Sprague-Dawley rats were modeled according to the Longa modified suture method	9 mg/kg/day, i.p. 7 days		Reduced the extent of cerebral infarction; promoted angiogenesis and neural function remodeling; increased VEGF, VEGFR, Notch1, and Notch4 expression in the brain tissue.	[55]
Cerebral vascular diseases	Male Sprague-Dawley rats were subjected to MCAO via electrocoagulation	2.5, 5.0, and 10.0 mg/kg/day, i.v. 14 days		Protected NVU structure; ameliorated damage to vascular and neuronal components; promoted neurogenesis and angiogenesis in the brain; activated the VEGF-PI3K/AKT and VEGF-MEK1/2/ERK1/2 pathways.	[56]
Cerebral vascular diseases	Sprague-Dawley rats were subjected to pMCAO via electrocoagulation	5 mg/kg/day, i.p. 7 days		Protected neurovascular unit lesions caused by focal cerebral ischemia; promoted the recovery of neurological function after cerebral ischemia.	[57]
Cerebral vascular diseases	Female and male Sprague-Dawley rats were subjected to MCAO via electrocoagulation	1, 3, and 5 mg/kg/day, i.p. 7 days		Promoted functional recovery of limb motor; promoted the maturation of neovascularization; upregulated the expression of Ang-1 and its receptor Tie-2.	[58]
Cerebral vascular diseases	Male Sprague-Dawley rats were subjected to I/R of the middle cerebral artery	16.4, 32.7, and 65.4 mg/kg/day lyophilized powder of catalpol and puerarin, i.v. 24 h		Ameliorated neurological deficiency; reduced the infarct volume; protected cerebral cells from apoptosis in ischemic area; improved the growth of the main cells of NVU in ischemic area; reduced the oxidative stress injury (e.g., reduction of MDA, LDH, and NO levels and increase of SOD levels); inhibited the inflammation (e.g., decrease of NF-κB/p65, TNF-α, IL-1β, and IL-6 levels); enhanced the favorable factors (e.g., EPO, EPOR, VEGF, and GAP-43).	[59]
Cerebral vascular diseases	Male Sprague-Dawley rats were subjected to MCAO via electrocoagulation	16.4, 32.7, and 65.4 mg/kg/day lyophilized powder of catalpol and puerarin, i.v. 14 days		Ameliorated cerebral ischemia (increased regional cerebral blood flow); reduced infarct volume; protected vessel integrity; inhibited endothelial cell apoptosis.	[60]
Heart diseases	Sprague-Dawley rats were subjected to ligate the anterior interventricular branch of the left coronary artery	1, 5, and 10 mg/kg/day, i.p. 7 days		Had protective effect against myocardial I/R injury (decrease of myocardial infarction area); improved free radicals and myocardial metabolism; inhibited myocardial apoptosis.	[61]
Heart diseases	Male Wistar rats were subcutaneously injected with ISO (85 mg/kg) at an interval of 24 h for 2 consecutive days to induce experimental myocardial infarction	5 and 10 mg/kg/day, i.p. 10 days		Ameliorated the ISO-induced cardiac dysfunction (e.g., increase of ± LVdp/dtmax and LVSP, decrease of LVEDP); inhibited cardiomyocyte apoptosis (reduction of TUNEL-positive cell percentage, alteration of Bax and Bcl-2 expression, and decrease of caspase-3 and caspase-9 activities); activated the apelin/APJ signing pathway.	[62]
Heart diseases	Male Sprague-Dawley rats were subjected to 30 min of myocardial ischemia via ligating left anterior descending coronary artery and then reperfused for 3 h	5 mg/kg, i.p., 5 min before reperfusion		Improved cardiac functions, reduced myocardial infarction, apoptosis, and necrosis of cardiomyocytes after I/R; reduced ONOO− formation; increased Akt and endothelial nitric oxide synthase phosphorylation, NO production, anti-oxidant capacity, and reduced MI/R-induced inducible nitric oxide synthase expression and ·O2− production in I/R hearts.	[63]
Heart diseases	Male C57BL/6 mice were subjected to ligate left anterior descending coronary artery for 45 min followed by 240 min of reperfusion	5 mg/kg, i.p. 15 min before reperfusion		Reduced myocardial damage; suppressed oxidative stress; repressed the production of different pro-inflammatory mediators; inhibited cardiomyocyte apoptosis; activated the Nrf2/HO-1 signaling pathway.	[64]
Heart diseases	Male Wistar rats were subcutaneously injected with ISO (85 mg/kg) at an interval of 24 h for 2 consecutive days to induce myocardial injury	2.5, 5, and 10 mg/kg/day, i.p. 10 days		Suppressed the histopathological changes including myocardial structure damage and leucocyte infiltration; decreased the levels of CK-MB, LDH, and MDA, and renewed the activities of SOD; inhibited the upregulation of the expressions of TNF-α and IL-1β.	[[65], [66]]
Heart diseases	Male Sprague-Dawley rats were subcutaneously injected with INN (10 mg/kg) on 19th, 20th, and 21st day to induce acute myocardial infarction	10, 20, and 40 mg/kg/day, i.g. 3 weeks		Reduced the abnormal raise in S-T segment; scavenged oxygen free radicals and reduced the production of oxidized products from lipids and the damage in cardiac tissues (e.g., returned the activities and levels of serum LDH, CK, SOD, and MDA); reduced the infract areas and improved the pathological status of the infracted tissues; activated Notch signal pathway to promote the differentiation and proliferation of endothelial cells in the infracted rats.	[67]
Heart diseases	Male Kunming nice were subcutaneously injected with ISO (2 μg/g) for 7 consecutive days to induce myocardial hypertrophy	90 μg/g/day, i.g. 7 days		Reduced the cardiac weight indexes; decreased the contents of MDA, cAMP, and Ang II in myocardium.	[68]
Heart diseases	Male C57BL/6 mice fed with high fat and high sugar diets were injected intraperitoneally with STZ (100 mg/kg)	10 mg/kg/day, i.g. 12 weeks		Improve left ventricular function (e.g., decrease of LVEDP levels and increases of LVSP and ± LVdp/dtmax); attenuated the extent of myocardial atrophy with decreased infiltration of inflammatory cells; inhibited cardiomyocyte apoptosis; alleviated myocardial injury via Neat1/miR-140–5p/HDAC4 axis.	[69]
Heart diseases	Male Wistar rats fed with high fat and high sugar diet were injected intraperitoneally with STZ (15 mg/kg)	2.5, 5, and 10 mg/kg/day, i.g. 12 weeks		Improved E/A and E/E′ of the cardiac function; decreased myocardial TGF-β1 expression.	[70]
Heart diseases	Male Sprague-Dawley rats fed with high fat and high sugar diets were injected intraperitoneally with STZ (15 mg/kg)	2.5, 5, and 10 mg/kg/day, i.g. 12 weeks		Reduced oxidative stress (e.g., decrease of myocardial MDA content and increase of myocardial SOD content); improved cardiac function (e.g., decrease of E/E′ value and IVRT and increase of E/A value).	[71]

ApoE: apolipoprotein E; i.g.: intragastrical; TG: triglyceride; TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; IL: interleukin; iNOS: inducible nitric oxide (NO) synthase; ERα: estrogen receptor α; TNF: tumor necrosis factor; MCP-1: monocyte chemotactic protein 1; sVCAM-1: soluble vascular cell adhesion molecule-1; sICAM-1: soluble intercellular adhesion molecule-1; VCAM: vascular cell adhesion molecule; MM-9: matrix metalloproteinase-9; LDLr: low-density lipoprotein receptor; SOD: superoxide dismutase; GSH: glutathione; MDA: malondialdehyde; LDH: lactate dehydrogenase; ROS: reactive oxygen species; PGC-1α: peroxisome proliferator-activated receptor-γ coactivator-1α; TRET: telomerase reverse transcriptase; GSH-Px: GSH peroxidase; STZ: streptozotocin; PGF2α: prostaglandin F2α; TGF: transforming growth factor; i.p.: intraperitoneal; pMCAO: permanent middle cerebral artery occlusion; CBF: cerebral blood flow; EPO: erythropoietin; EPOR: EPO receptor; VEGF: vascular endothelial growth factor; i.v.: intravenous; HIF-1α: hypoxia inducible factor 1α; VEGFR: VEGF receptor; NVU: neurovascular unit; MCAO: middle cerebral artery occlusion; Ang-1: angiopoietin-1; Tie-2: tyrosine kinase-2; I/R: ischemic/reperfusion; ISO: isoproterenol; ±LVdp/dt_max: left ventricular maximum rate of positive or negative pressure development; LVSP: LV systolic peak pressure; LVEDP: left ventricular end-diastolic pressure; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling; MI/R: myocardial ischemia/reperfusion; CK-MB: creatine kinase-MB; CK: creatine kinase; cAMP: cyclic adenosine monophosphate; E/A: ratio of early diastolic blood flow velocity (E) to late diastolic blood flow velocity (A); E/E': the ratio of early diastolic transmitral velocity to early diastolic mitral annular velocity; IVRT: isovolumic relaxation time.