Coronary Microvascular Smooth Muscle Cells Contribute to Heart Failure in Diabetes Mellitus by Increasing Methylglyoxal Flux

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 490-P
Author(s):  
KESHORE BIDASEE
Keyword(s):  
Diabetes Mellitus ◽  
Heart Failure ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells

Abstract MP19: Smooth Muscle Cell Cytochrome B5 Reductase 3 Causes Heart Failure With Reduced Ejection Fraction Under Hypoxic Stress

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Brittany G Durgin ◽  
Adam C Straub ◽  
Katherine C Wood ◽  
Scott A Hahn
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Ejection Fraction ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Cytochrome B5 ◽  
Muscle Cells ◽  
Right Heart

Pulmonary hypertension causes increased pulmonary vascular resistance and right heart failure. Nitric oxide (NO) binds to its receptor soluble guanylyl cyclase (sGC) within vascular smooth muscle cells in its reduced heme (Fe 2+ ) form to increase intracellular cGMP production, activate protein kinase G signaling, and induce vessel relaxation. In pulmonary hypertension, endothelial damage leading to decreased NO bioavailability combined with oxidation of the sGC heme (Fe 3+ ) in vascular smooth muscle cells rendering it NO-insensitive results in vasonstriction. Notably, we have previously shown that cytochrome b5 reductase 3 (CYB5R3) in vascular smooth muscle cells is an sGC reductase (Fe 3+ to Fe 2+ ) that maintains NO-dependent vasodilation in vascular disease. We therefore hypothesized that CYB5R3 confers protection in pulmonary hypertension. To test this, we subjected smooth muscle cell-specific CYB5R3 knockout mice (SMC CYB5R3 KO) to 21 days of continuous hypoxia (10% O 2 ) and assessed vascular and cardiac function. We found that SMC CYB5R3 KO led to enhanced cardiac hypertrophy when compared to wild-type (WT) controls (n=8/ group). Specifically, SMC CYB5R3 KO mice had a larger right ventricle per tibia size, left ventricle mass, and Fulton index compared to WT (n=8/ group). Moreover, SMC CYB5R3 KO mice had a significantly impaired ejection fraction and fractional shortening, and increased left ventricular posterior wall pressure (n=3-5/group). No differences in right heart function or overall cardiac fibrosis were observed between groups (n=3-5/group). With respect to vascular function, hypoxic pulmonary arteries from SMC CYB5R3 KO mice also had a blunted response to sodium nitroprusside induced NO-dependent vasodilation though no difference in sGC activator BAY 58-2667 induced NO-independent vasodilation was observed as compared to WT (n=8-11/ group). No differences in pulmonary arterial sGC levels or medial area were observed between groups (n=6-7). Combined, these data implicate that loss of SMC CYB5R3 exacerbates cardiomyocyte hypertrophy and reduces cardiac function independent of pulmonary pressure differences.

scholarly journals Expression of Angiotensin II Type 1 Receptor in Rat Bladder Smooth Muscle Cells in Response to a Streptzotocin Induced Diabetes Mellitus Model

2012 ◽  
Vol 6 (2) ◽  
pp. 62-66 ◽  
Author(s):  
Shohei Tobu ◽  
Mitsuru Noguchi ◽  
Teppei Hatada ◽  
Ken-ichi Mori ◽  
Manabu Matsuo ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Bladder Smooth Muscle ◽  
Rat Bladder

Abstract 1: Deletion of the Mapk-p38 From Vascular Smooth Muscle Cells and Cardiomyocytes Causes Hypotension and Dilated Cardiomyopathy in Angiotensin II Dependent Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Susanne Mende ◽  
Katharina Bottermann ◽  
Stefanie Stamer ◽  
Manuel Thieme ◽  
Axel Gödecke ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Dilated Cardiomyopathy ◽  
Vascular Smooth Muscle Cells ◽  
Vascular Injury ◽  
Muscle Cells ◽  
Ang Ii

The heart and the vasculature are key targets of angiotensin (Ang) II. In this regard, Ang II acting via Ang II type 1 (AT1)-receptors induces hypertension, cardiac hypertrophy and vascular injury. Since AT1-receptor stimulation have been shown to activate the mitogen activated protein kinase (MAPK) p38 leading to hypertrophy, migration and remodelling in cardiomocytes and vascular smooth muscle cells (VSMC)s in vitro, the MAPK p38 is considered as a major contributor in Ang II mediated cardiac and vascular injury. In order to investigate its role in Ang II dependent hypertension, we generated mice lacking p38alpha only in VSMC and cardiomyocytes (p38KO) using Cre-Loxp technology with a KISM22-cre transgene on a Bl6/C57 background. The specificity of p38alpha deletion was verified by western blot analysis. While cardiac function did not differ between both groups, blood pressures (BPs) were significantly lower under baseline conditions in p38KO mice compared to controls (106.4±5.2 vs. 123.6±5.4 mmHg; p<0.05). To test whether p38KO mice were protected from hypertensive heart failure and vascular injury, we infused Ang II (1000ng/kg/min) for 2 weeks. Ang II infusion caused a significantly attenuated increase in BPs in p38KOs than in controls (117.9±9.7 vs. 148.0±18.8mmHg; p<0.001). This effect could not be explained by an attenuated vascular response to Ang II in p38KOs, as acute pressor responses to Ang II in vivo and in the isolated perfused kidney as well as changes in renal blood flow were not attenuated in p38KO compared to controls. Surprisingly, in p38KOs, chronic Ang II infusion caused exaggerated cardiac fibrosis and severe dilated cardiomyopathy which was already apparent on day two after Ang II infusion (ejection fraction: 26.6±8.5 (p38KO) vs. 60.8±9.6% (control); p <0.001, diastolic volume: 116.9±8.6 vs. 60.2±7.6μl, p <0.001; systolic volume: 88.9±10.3 vs. 24.6±6.7μl, p <0.001). In summary, these results suggest a divergent role of p38 in regulating blood pressure and in the pathogenesis of heart failure as Ang II induces blood pressure independent dilated cardiomyopathy in p38KO mice. However, more studies are necessary to reveal the underlying mechanism.

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