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Toll-like receptor 9 (TLR9) is a member of the innate immune system and has been shown to influence myocardial function, but its role in myocarditis is hitherto unknown. We therefore investigated whether or not TLR9 plays a role in this disease in coxsackievirus B3 (CVB3)induced myocarditis in mice. Left ventricular (LV) function, cardiac immune cell infiltration, vires mRNA, and components of the TLR9 downstream pathway were investigated in TLR9-deficient [knockout (KO)] and wild-type (WT) mice after infection with CVB3. Murine cardiac TLR9 expression was significantly increased in WT mice with acute CVB3 infection but not in WT mice with chronic myocarditis. Furthermore, in the acute phase of CVB3-induced myocarditis, CVB3-infected KO mice displayed improved LV function associated with reduced cardiac inflammation indexed by reduced amounts of immune cells compared with CVB3-infected WT mice. In contrast, in the chronic phase, LV function and inflammation were not seen to differ among the infected groups. The cardioprotective effects due to TLR9 deficiency were associated with suppression of the TLR9 downstream pathway as indexed by reduced cardiac levels of the adapter protein myeloid differentiation factor (MyD)-88 and the proinflammatory cytokine TNF-[alpha]. In addition, TLR9 deficiency led to an activation of the antiviral cytokine interferon-[beta] in the heart as a result from viral infection. In conclusion, the MyD88/TNF-[alpha] axis due to TLR9 activation in the heart contributes the development of acute myocarditis but not of chronic myocarditis. heart failure; inflammation; innate immunity doi: 10.1152/ajpheart.01188.2009.

Abstract: Endothelin-1 (ET-1) exhibits potent proinflammatory and profibrotic properties. Moreover, inflammation is a potent stimulus for inducible NO synthase (iNOS), which has been shown to contribute to cardiac injury. We [...]

Diabetes mellitus impairs the cardiac kallikrein-kinin system by reducing cardiac kallikrein (KLK) and kininogen levels, a mechanism that may contribute to the deleterious outcome of cardiac ischemia in this disease. We studied left ventricular (LV) function and bradykinin (BK) coronary outflow in buffer-perfused, isolated working hearts (n = 7) of controls and streptozotocin (STZ)-induced diabetic rats before and after global ischemia. With the use of selective kininase inhibitors, the activities of angiotensin I-converting enzyme, aminopeptidase P, and neutral endopeptidase were determined by analyzing the degradation kinetics of exogenously administered BK during sequential coronary passages. Basal LV function and coronary flow were impaired in STZ-induced diabetic rats. Neither basal nor postischemic coronary BK outflow differed between control and diabetic hearts. Reperfusion after 15 min of ischemia induced a peak in coronary BK outflow that was of the same extent and duration in both groups. In diabetic hearts, total cardiac kininase activity was reduced by 41.4% with an unchanged relative kininase contribution compared with controls. In conclusion, despite reduced cardiac KLK synthesis, STZ-induced diabetic hearts are able to maintain kinin liberation under basal and ischemic conditions because of a primary impairment or a secondary downregulation of kinin-degrading enzymes. bradykinin; kininase; myocardial ischemia

Natriuretic and blood pressure changes due to hypertonic saline injections in brain are controlled by a central angiotensinergic mechanism. There is a concentration-dependent increase of renal sodium excretion after bolus injections of hypertonic saline. There is a notable increase in mean arterial blood pressure (MAP) after injection of two highest saline concentrations. High saline concentration in cerebrospinal fluid causes angiotensin II-controlled natriuresis.

Proteomic Analysis Reveals Upregulation of ACE2 (Angiotensin-Converting Enzyme 2), the Putative SARS-CoV-2 Receptor in Pressure-but Not Volume-Overloaded Human Hearts ACE2 expression values from (B) protein measurements as log2 label-free-quantification intensities (n=41 aortic stenosis [AS], 17 mitral valve regurgitation [MR], 17 control [CON]), and (C) RNA sequencing as log2 counts per million (n=17 AS, 6 CON). Moreover, there was a significant correlation between ACE2 protein abundance and mRNA expression levels ( I R i =0.6, I P i <0.01) suggesting a direct link between cardiac ACE2 transcription levels and the amount of generated ACE2. [Extracted from the article]

The article presents a study on the effects of angiotensin, Ang-(1-7), produced by the heart or by the injection in heart failure development induced by myocardial infarction (MI). The study uses the investigation of Ang-(1-7) in bone marrow-derived mononuclear cells of rodents, and Ang-(1-7) produced by heart or injection. The study shows effects of Ang-(1-7) including increased vascular endothelial growth factor-positive results, inhibited cardiac hypertrophy, and improved cardiac function.

Objective: Myocardial collagen degradation is regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs). The possible relevance of MMPs in association with the inflammatory induction was investigated in a murine coxsackievirus B3 myocarditis model. Methods: Hearts from viral infected and sham-infected BALB/c mice were analyzed by semi-quantitative RT-PCR, picrosirius red staining, Western blot analysis, and immunohistochemistry. Results: In viral infected mice, both mRNA and protein abundance for collagen type I remained unaltered. In addition, picrosirius red staining showed the unchanged total collagen content. However, degraded soluble fraction of collagen type I protein was increased. Moreover, the mRNA abundance for MMP-3 and MMP-9 was upregulated, whereas the mRNAs for TIMP-1 and TIMP-4 were downregulated, respectively. The upregulation of MMP-3/MMP-9 and downregulation of TIMP-4 were confirmed at the protein level, and were associated with significantly increased mRNA levels of interleukin 1β, tumor necrosis factor-α, transforming growth factor-β1 and interleukin-4. Conclusion: The increment of MMPs in the absence of counterbalance by TIMPs may lead to a functional defect of the myocardial collagen network by posttranslational mechanisms. This may contribute significantly to the development of left ventricular dysfunction in murine viral myocarditis. The inflammatory response with induction of cytokines may mediate the dysregulation of the myocardial MMP/TIMP systems. [Copyright &y& Elsevier]

Looks at a study on the improvement of defective sarcoplasmic reticulum Ca2+ transport in diabetic heart of transgenic rats expressing the human kallikrein-1 gene. Findings of the study; Conclusions and significance of the study.