1. Genetic Models of Hypertension

Genetic hypertension models can simulate the genetic phenomena in humans, among which the spontaneously hypertensive rat (SHR) is the most commonly used.

The blood pressure level in adult SHR rats is generally > 200 mmHg (1 mmHg = 0.133 kPa). There is no clear evidence of pathological disorder in the early stage, but later on, target organ damage due to hypertension occurs. The SHR rat is currently recognized both domestically and internationally as the animal model closest to human primary hypertension^[1][2].

2. Induced Models of Hypertension

•Renoprival Hypertension Model: It can be achieved by reducing blood flow in the renal artery or main renal artery, either by resection or non-resection of renal masses, inducing compression of renal parenchyma, performing subtotal nephrectomy, or by denervation of the baroreceptors in the aorta. This approach is applicable to both small and large animal models.

•Ang II–Dependent Hypertension Model: The Renin-Angiotensin-Aldosterone System (RAAS) plays a fundamental role in the normal regulation of sodium and water homeostasis. Therefore, long-term subcutaneous infusion of angiotensin II is one of the most widely used preclinical models for hypertension in rodents.

•Mineralocorticoid-Salt Hypertension Model: The combination of mineralocorticoids and a high-salt diet can induce hypertension in both large and small animals. In animals with high salt intake, administration of deoxycorticosterone (usually in the form of DOCA) is the most commonly used method to induce mineralocorticoid-salt hypertension.

In addition, there are models such as renal hypertension models, nitric oxide-induced models, and obesity-related hypertension models.

1. Models of Atherothrombotic Disease

Mouse models have proved to be useful to study development and progression of atherosclerotic lesion. As wild-type mice are resistant to lesion development, the current mouse models for atherosclerosis are based on genetic modifications of lipoprotein metabolism with additional dietary changes. Among them, low-density lipoprotein receptor-deficient mice (LDLR^−/− mice) and apolipoprotein E-deficient mice (Apoe^−/−mice) are the most widely used^[2].

Diabetes is a high risk factor of cardiovascular disease. The cardiovascular complications of diabetes are manifested primarily as ischemic heart disease caused by accelerated atherosclerosis, and also as cardiomyopathy. Several models are available to study atherosclerosis and cardiomyopathy associated with diabetes, including Apoe^−/−and LDLR^−/− mice in which type 1 diabetes is induced by streptozotocin or viral injection, thereby mimicking the accelerated atherosclerosis seen in patients with type 1 diabetes.

2. Models of Abdominal Aortic Aneurysms (AAAs)

Abdominal Aortic Aneurysms (AAA) are a degenerative vascular disease and a potentially life-threatening condition. The primary characteristics of AAA include loss of vascular smooth muscle cells (VSMCs), degradation of the extracellular matrix (ECM), increased infiltration of inflammatory cells, and aberrant oxidative stress^[3].

Animal models of atherothrombotic AAA are essential tools for the preclinical evaluation of new therapeutic strategies for the suppression of aneurysmal degeneration. The mouse has become the preferred model for cardiovascular research for several reasons, including the ease of handling, low procedure costs, and the ability to manipulate the mouse genome.

Common AAA models include those induced by calcium chloride, elastase, Angiotensin II, and spontaneous mouse mutants.

3. Models of Heart Failure

Rat models have dominated research into heart damage. Myocardial damage in rat hearts is induced by three procedures: surgical, pharmacological, or electrical.

In surgical methods, left coronary artery ligation is the most common method used to induce acute myocardial damage in rat and other animal models. Additionally, cardiac injury can be induced pharmacologically, such as the beta-one adrenergic receptor (B-AR) agonist isoproterenol. Isoproterenol administration before ischemia exerts a cardioprotective action in rats, but at the right dose it induces cardiac myocyte necrosis and extensive LV dilatation and hypertrophy. Isoproterenol treatment and left coronary artery ligation in rats are efficient and reproducible methods.

In addition, the electrical method consists of generating overlapping burns in exposed rat hearts by applying a 2-mm-tipped soldering iron to the epicardium of the left ventricle. While this is also a valid method, the degree of heart damage produced is not consistent among laboratories, limiting the reproducibility of the results obtained with this procedure^[2].

1. Angiotensin II human

• Angiotensin II-Induced AAA Model

Osmotic pump subcutaneous infusion of Angiotensin II (AngII) is a reliable and reproducible technique that can be used to induce abdominal and thoracic aortic aneurysms in mice (Click here to view detailed reference steps)^[3].

Studies have confirmed that 9–12- week-old male Apoe^−/−mice were subcutaneously infused with either saline or MCE Ang II (HY-13948) (1000 ng/kg per min) for 4 weeks to induce AAA model ^[4]. After 4 weeks, the suprarenal aortic segments revealed significant increases in the inner abdominal aortic diameter, marked degradation of elastic laminae, and collagen deposition in the medial layer in Ang II-treated mice.

• Angiotensin II-Induced Hypertension Model

Research has confirmed that in C67BL/6J mice (aged 10-12 weeks, weighing 20-22 g), infusion of MCE Ang II (HY-13948) at a dose of 1.44 mg/kg body weight/d for 28 days^[5]. Mice pumped with Ang II had significantly higher blood pressure.

• Angiotensin II-Induced Hypertension Model

Male C57BL/6 mice (20 −23 g, 6–8 weeks) were infused with MCE Ang II (HY-13948) at a dose of 500 ng/kg/min by an osmotic mini-pump implanted through the back of the neck. 2 weeks later, Ang II infusion led to LV hypertrophy, cardiac dysfunction, apparently increased cross-sectional area, reduced intercellular space, and significantly increased myocardial fibrosis in cardiac tissues of mice^[5].

2. L-NAME hydrochloride

• L-NAME-induced Hypertension Model

Male eight-week-old Apoe^−/−mice with a C57BL/6 background fed a HFD and intraperitoneally injected with MCE L-NAME (HY-18729A) (20 mg/kg/D) for 12 weeks. The results demonstrated that L-NAME not only increased arterial blood pressure in mice, but also increased the levels of TG, TC and LDL while decreasing the level of HDL in the serum, and increased the aortic lesions in multiple arterial beds by approximately 20 %^[6].

3. Doxorubicin hydrochloride (DOX)

• DOX-induced Cardiotoxicity Model

Doxorubicin hydrochloride (DOX) is a potent anticancer chemotherapeutic agent, the clinical application of which is greatly limited by its cardiotoxicity, and it is subsequently used to induce cardiotoxicity in mouse models^[7].

Male C57BL/6J mice (6–8-week-old) weighing 20 ± 2 mg were administered intraperitoneally with MCE (DOX)(HY-15142) at a concentration of 3 mg/kg every two days for two consecutive weeks (until the cumulative dose reached 21 mg/kg body weight) to generate cardiotoxicity mice models. The results demonstrated that the model mice exhibited cardiac dysfunction, severe myocardial fibre disruption and cardiac atrophy^[7].

• DOX-induced Heart Failure Model

Research has confirmed that in male C57BL/6J mice (aged 8 weeks), the administration of MCE (DOX)(HY-15142) at a dose of 5 mg/kg via weekly intraperitoneal injection once a week for consecutive 4 weeks can induce heart failure mouse model^[9].After 4 weeks, the cardiac function indexes LVFS, LVEF and heart rate were decreased, heart size and the ratio of heart weight to body weight (HW/BW) were reduced, cardiac atrophy was evident, and myocardial fibrosis in cardiac tissue was significantly enhanced in model group.

4. Monocrotaline (MCT)

• MCT-induced Pulmonary Arterial Hypertension Model

Sprague Dawley rats (male, ~200–250 g) were intraperitoneally injected with 50 mg per kg body weight MCE product MCE Monocrotaline (MCT)(HY-N0750), allowed to develop pulmonary hypertension (PH) from days 0 to 21^[10]. The results showed that after 3 weeks, the rats in the model group had weakened cardiac function, and there was evident pulmonary vascular remodeling, with significant changes in the proportion of non-muscled, partially muscled, or fully muscled pulmonary arterioles.

5. Norepinephrine (NE)

• NE-induced Cardiac Hypertrophy Model

Research has confirmed that cardiac hypertrophy in mice was induced by subcutaneous injection of MCE product NE (HY-13715) (1.5 mg/kg, dissolved with 0.1%Vc) twice daily for 15 uninterrupted days^[10]. After 15 days, the mice in the model group showed obviously reduced the left ventricular contractile function and increased the LVPW thickness. NE significantly induced an increase in the heart size, markedly increased the cross-sectional area of cardiomyocytes, indicating significant symptoms of cardiac hypertrophy.

Animal models of cardiovascular disease have provided important insights into the genetic basis of human cardiovascular disease and have provided testing platforms for drugs and therapeutic approaches. Despite partial limitations, animal models remain the best tools to advance the understanding of the mechanisms of human cardiovascular disease. Everyone can choose the best modeling method according to their own research purposes.