No abstract

Reduced levels of adiponectin (APN) contribute to cardiovascular injury in the diabetic population. Recent studies demonstrate elevated circulating APN levels are associated with endothelial dysfunction during pre-diabetes, suggesting the development of APN resistance. However, mechanisms leading to, and the role of, vascular APN resistance in endothelial dysfunction remain unidentified. The current study determined whether diabetes cause endothelial APN resistance, and by what mechanisms. Under high glucose/high lipids (HG/HL), APN-stimulated nitric oxide production by HUVEC was decreased, phosphorylation of eNOS, AMPK, and Akt was attenuated (P<0.01), and APN’s anti-TNFα effect was blunted (P<0.01). APN receptor expression remained normal, whereas Cav1 expression was reduced in HG/HL cells (P<0.01). The AdipoR1/Cav1 signaling complex was dissociated in HG/HL cells. Knock-down of Cav1 inhibited APN’s anti-oxidative and anti-inflammatory actions. Conversely, preventing HG/HL-induced Cav1 downregulation by Cav1 overexpression preserved APN signaling in HG/HL cells. Knock-in of a wild type Cav1 in Cav1 knock-down cells restored caveolae structure and rescued APN signaling. In contrast, knock-in of a mutated Cav1 scaffolding domain restored caveolae structure, but failed to rescue APN signaling in Cav1 knock-down cells. Finally, AdipoR1/Cav1 interaction was significantly reduced in diabetic vascular tissue, and the vasorelaxative response to APN was impaired in diabetic animals. The current study demonstrates for the first time the interaction between AdipoR1 and Cav1 is critical for adiponectin-mediated vascular signaling. The AdipoR1/Cav1 interaction is adversely affected by HG/HL, due largely to reduced Cav1 expression, supporting a potential mechanism for the development of APN resistance, contributing to diabetic endothelial dysfunction.

Platelet activation is important in hypertension-induced cardiac inflammation and fibrosis. P-selectin expression significantly (P<0.05) increases when platelets are activated during hypertension. Although P-selectin recruits leukocytes to sites of inflammation, the role of P-selectin in cardiac inflammation and fibrosis remains to be elucidated. The present study aimed to investigate whether platelet-derived P-selectin promotes hypertensive cardiac inflammation and fibrosis. P-selectin knockout (P-sel KO) mice and wild-type (WT) C57BL/6 littermates were infused with angiotensin II (Ang II) at 1,500 ng/kg/min for 7 days and then cross-transplanted with platelets originating from either WT or P-sel KO mice. P-selectin expression was increased in the myocardium and plasma of hypertensive mice, and the P-sel KO mice exhibited significantly (P<0.05) reduced cardiac fibrosis. The fibrotic areas were markedly smaller in the hearts of P-sel KO mice compared with WT mice, as assessed by Masson's trichrome staining. In addition, α-smooth muscle actin and transforming growth factor β1 (TGF-β1) expression levels were decreased in the P-sel KO mice, as assessed by immunohistochemistry. Following platelet transplantation into P-sel KO mice, the number of Mac-2 (galectin-3)- and TGF-β1-positive cells was increased in mice that received WT platelets compared with those that received P-sel KO platelets, and the mRNA expression levels of collagen I and TGF-β1 were also increased. The results from the present study suggest that activated platelets secrete P-selectin to promote cardiac inflammation and fibrosis in Ang II-induced hypertension.

The purpose of the present study was to investigate the effects on blood pressure and myocardial hypertrophy in SHRs (spontaneously hypertensive rats) of RNAi (RNA interference) targeting ACE (angiotensin-converting enzyme). SHRs were treated with normal saline as vehicle controls, with Ad5-EGFP as vector controls, and with recombinant adenoviral vectors Ad5-EGFP-ACE-shRNA, carrying shRNA (small hairpin RNA) for ACE as ACE-RNAi. WKY (Wistar-Kyoto) rats were used as normotensive controls treated with normal saline. The systolic blood pressure of the caudal artery was recorded. Serum levels of ACE and AngII (angiotensin II) were determined using ELISA. ACE mRNA and protein levels were determined in aorta, myocardium, kidney and lung. On day 32 of the experiment, the heart was pathologically examined. The ratios of heart weight/body weight and left ventricular weight/body weight were calculated. The serum concentration of ACE was lower in ACE-RNAi rats (16.37+/-3.90 ng/ml) compared with vehicle controls and vector controls (48.26+/-1.50 ng/ml and 46.67+/-2.82 ng/ml respectively; both P<0.05), but comparable between ACE-RNAi rats and WKY rats (14.88+/-3.15 ng/ml; P>0.05). The serum concentration of AngII was also significantly lower in ACE-RNAi rats (18.24+/-3.69 pg/ml) compared with vehicle controls and vector controls (46.21+/-5.06 pg/ml and 44.93+/-4.12 pg/ml respectively; both P<0.05), but comparable between ACE-RNAi rats and WKY rats (16.06+/-3.11 pg/ml; P>0.05). The expression of ACE mRNA and ACE protein were significantly reduced in the myocardium, aorta, kidney and lung in ACE-RNAi rats compared with that in vehicle controls and in vector controls (all P<0.05). ACE-RNAi treatment resulted in a reduction in systolic blood pressure by 22+/-3 mmHg and the ACE-RNAi-induced reduction lasted for more than 14 days. In contrast, blood pressure was continuously increased in the vehicle controls as well as in the vector controls. The ratios of heart weight/body weight and left ventricular weight/body weight were significantly lower in ACE-RNAi rats (3.12+/-0.23 mg/g and 2.24+/-0.19 mg/g) compared with the vehicle controls (4.29+/-0.24 mg/g and 3.21+/-0.13 mg/g; P<0.05) and the vector controls (4.43+/-0.19 mg/g and 3.13+/-0.12 mg/g; P<0.05). The conclusion of the present study is that ACE-silencing had significant antihypertensive effects and reversed hypertensive-induced cardiac hypertrophy in SHRs, and therefore RNAi might be a new strategy in controlling hypertension.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has rapidly become a global health emergency. In addition to causing respiratory effects, SARS-CoV-2 can result in cardiac involvement leading to myocardial damage, which is increasingly being explored in the literature. Myocardial injury is an important pathogenic feature of COVID-19. The angiotensin-converting enzyme-2 receptor plays a key role in the pathogenesis of the virus, serving as a “bridge” allowing SARS-CoV-2 to invade the body. However, the exact mechanism underlying how SARS-CoV-2 causes myocardial injury remains unclear. This review summarizes the main possible mechanisms of myocardial injury in patients with COVID-19, including direct myocardial cell injury, microvascular dysfunction, cytokine responses and systemic inflammation, hypoxemia, stress responses, and drug-induced myocardial injury. Understanding of the underlying mechanisms would aid in proper identification and treatment of myocardial injury in patients with COVID-19.