Metformin is an antidiabetic drug. However, the pleiotropic beneficial effects of metformin in nondiabetic models still need to be defined. The objective of this study is to investigate the effect of metformin on angiotensin II (Ang II)-induced hypertension and cardiovascular diseases. Mice were infused with Ang II (400 ng/kg per min) with or without metformin for 2 weeks. Mice infused with angiotensin II displayed an increase in blood pressure associated with enhanced vascular endoplasmic reticulum (ER) stress markers, which were blunted after metformin treatment. Moreover, hypertension-induced reduction in phosphorylated AMPK, endothelial nitric oxide synthase (eNOs) phosphorylation, and endothelium-dependent relaxation (EDR) in mesenteric resistance arteries (MRA) were rescued after metformin treatment. Infusion of ER stress inducer (tunicamycin, Tun) in control mice induced ER stress in MRA and reduced phosphorylation of AMPK, eNOS synthase phosphorylation, and EDR in MRA without affecting systolic blood pressure (SBP). All these factors were reversed subsequently with metformin treatment. ER stress inhibition by metformin improves vascular function in hypertension. Therefore, metformin could be a potential therapy for cardiovascular diseases in hypertension independent of its effects on diabetes.

Over the past three decades, the increasing rates of obesity have led to an alarming obesity epidemic worldwide. Obesity is associated with an increased risk of cardiovascular diseases; thus, it is essential to define the molecular mechanisms by which obesity affects heart function. Individuals with obesity and overweight have shown changes in cardiac structure and function, leading to cardiomyopathy, hypertrophy, atrial fibrillation, and arrhythmia. Autophagy is a highly conserved recycling mechanism that delivers proteins and damaged organelles to lysosomes for degradation. In the hearts of patients and mouse models with obesity, this process is impaired. Furthermore, it has been shown that autophagy flux restoration in obesity models improves cardiac function. Therefore, autophagy may play an important role in mitigating the adverse effects of obesity on the heart. Throughout this review, we will discuss the benefits of autophagy on the heart in obesity and how regulating autophagy might be a therapeutic tool to reduce the risk of obesity-associated cardiovascular diseases.

MiR-204 is expressed in vascular smooth muscle cells (VSMC). However, its role in VSMC contraction is not known. We determined if miR-204 controls VSMC contractility and blood pressure through regulation of sarcoplasmic reticulum (SR) calcium (Ca 2+ ) release. Systolic blood pressure (SBP) and vasoreactivity to VSMC contractile agonists (phenylephrine (PE), thromboxane analogue (U46619), endothelin-1 (ET-1), angiotensin-II (Ang II) and norepinephrine (NE) were compared in aortas and mesenteric resistance arteries (MRA) from miR-204 −/− mice and wildtype mice (WT). There was no difference in basal systolic blood pressure (SBP) between the two genotypes; however, hypertensive response to Ang II was significantly greater in miR-204 −/− mice compared to WT mice. Aortas and MRA of miR-204 −/− mice had heightened contractility to all VSMC agonists. In silico algorithms predicted the type 1 Inositol 1, 4, 5trisphosphate receptor (IP 3 R1) as a target of miR-204. Aortas and MRA of miR-204 −/− mice had higher expression of IP 3 R1 compared to WT mice. Difference in agonist-induced vasoconstriction between miR-204 −/− and WT mice was abolished with pharmacologic inhibition of IP 3 R1. Furthermore, Ang II-induced aortic IP 3 R1 was greater in miR-204 −/− mice compared to WT mice. In addition, difference in aortic vasoconstriction to VSMC agonists between miR-204 −/− and WT mice persisted after Ang II infusion. Inhibition of miR-204 in VSMC in vitro increased IP 3 R1, and boosted SR Ca 2+ release in response to PE, while overexpression of miR-204 downregulated IP 3 R1. Finally, a sequence-specific nucleotide blocker that targets the miR-204-IP 3 R1 interaction rescued miR-204-induced downregulation of IP 3 R1. We conclude that miR-204 controls VSMC contractility and blood pressure through IP 3 R1-dependent regulation of SR calcium release.

The extra energy required for synthesis and maintenance of new tissue increases the REE during pregnancy. The net change may vary 8‐fold with higher increases seen in obese than non‐obese women. Our objective was to identify body composition and hormonal factors influencing the REE of obese women during the last half of pregnancy. A total of 64 women with BMI >25 kg/m2 , 18‐42 years of age, and no history of chronic disease were recruited at 20 weeks gestation. Three were eliminated due to extreme obesity (BMI=53 kg/m2) and 2 for missing values giving a total of 59 participants. REE, body composition, and insulin resistance (HOMA‐IR), prolactin, progesterone, estradiol, leptin, adiponectin, and IGF‐1 were measured at 20, 28, and 34 weeks gestation. During the 14‐wk study, the REE increase averaged 200 kcal/d. The change varied from a 400 kcal/d decrease to a 590 kcal/d increase. Multivariant models predicted 62% of the variability in REE at 20 weeks, 41% at 28 and 34 weeks, and 24% of the change in REE from 20 to 34 weeks. Significant determinants varied with time of pregnancy: FM, FFM, progesterone and prolactin at 20 wks; FM and FFM at 28 wks; FM, FFM, and IGF‐1 at 34 wks; and FFM and IGF‐1 change predicted the REE change from 20 to 34 wks. Body composition and metabolic hormones only explained 24 to 60% of the REE variability in obese pregnant women suggesting that other factors play a role. Grant Funding Source: NIH Grant R01HD46741.

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